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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

Stephan Niland, Andrea Ximena Riscanevo, Johannes Andreas Eble

International Journal of Molecular Sciences · 2021 · Review · CC BY

Abstract

Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell–matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Solid tumors are complex structures of cancerous cells that are surrounded by a vascularized dynamic tumor stroma containing various non-malignant cells such as fibroblasts and myeloid cells. The prevailing conditions are similar to the inflammatory reaction during wound healing and favor angiogenesis, extracellular matrix (ECM) remodeling, and tumor cell motility. Carcinogenesis and cancer progression depend on 10 classic hallmarks, plus four additional hallmarks for metastasis, i.e., invasive motility, modulation of the microenvironment, plasticity, and colonization. Since proliferation and motility are fundamental properties of all cells, carcinogenesis is due to changes in the mutual interactions between cells and, in particular, with their ECM.

2The events that lead to metastasis are generally similar for all types of solid tumors and rely heavily on matrix-metalloproteinases (MMPs), even if the causes for tumorigenesis diverge in different types of cancer. After a precancerous cell has undergone epithelial-to-mesenchymal transition (EMT) and has become cancerous, it breaches the basement membrane (BM) and invades the stromal ECM, which becomes possible by reorganization of integrin-containing cell-matrix adhesome structures and recruitment of ECM-degrading MMPs to them. Invasion is also promoted by tumor-induced immune tolerance and an acidic microenvironment as a consequence of an altered metabolism with lactate secretion and an upregulated proton efflux pump NHE1 in tumors. Vascular dissemination and anoikis resistance are a consequence of upregulated tumor angiogenesis, attenuated apoptotic pathways, and upregulated integrin expression and phosphorylation of the Src-kinase-associated CUB domain-containing protein 1 (CDCP1). The last step in metastasis is extravasation and implantation into the pre-metastatic niche, supported by recruitment of mesenchymal stem cells and expression of chemokines and growth factors, as well as upregulated stem cell renewal pathways.

3The tumor microenvironment (TME) is formed by cells as well as by biochemical and biophysical components of the ECM and their intricate interactions in and around a solid tumor mass. Tumor progression and metastasis depend on highly regulated and complex remodeling of the TME by pericellular proteolysis, i.e., cleavage, processing, or shedding of cell adhesion molecules, growth factors, cytokines, and kinases. This pericellular proteolysis can have both tumor-promoting and tumor-suppressive effects, which is why the mutual influence of cancer cells and the TME has become the focus of interest. The ECM and its remodeling play an essential role in tumor dissemination, metastasis, and the formation of suitable metastatic niches.

4Integrins as the essential matrix receptors mediate cell adhesion and enable migration through the meshwork of the ECM. Via integrin-mediated adhesion, cells perceive the surrounding ECM, react to its different properties, and interact with it with amazing specificity, which is particularly significant for cancer onset, progression, and metastatic dissemination.

5Depending on the strength of the ECM, the migration of cancer cells is enabled or supported by the selective and specific proteolysis of certain matrix components. For example, the dense network of the BM must be broken early in the metastatic cascade. MMPs are of great importance in this context. Thus, they promote tumor development by regulating/contributing to increased invasiveness and the growth of metastatic tumors. MMP-14, in particular, as the only membrane-bound collagenase, plays a decisive role in this. However, the diverse MMP functions in the TME go far beyond mere remodeling.

6Various proteases, such as soluble and membrane-bound MMPs, soluble ADAMTs (a disintegrin and metalloproteinase with thrombospondin motifs) and transmembrane ADAMs (a disintegrin and metalloproteinase), cathepsins, bone morphogenetic protein 1, and Tolloid-like proteinases, as well as hyaluronidase and heparanase are involved in the formation and shaping of the TME in a variety of ways. In the metastatic cascade, they are significantly involved in cancer cell invasion and metastasis. Among the various extracellular proteases, MMPs are of outstanding importance, as they considerably affect the integrity of the ECM, the phenotype, and behavior of matrix-embedded cells and tissue turnover by degrading ECM proteins and selectively releasing cell surface-bound cytokines, growth factors, or their receptors. Depending on their type, these can have gelatinolytic and even collagenolytic activity towards the ECM. Of particular importance is MMP-14 (MT1-MMP), which is usually found at a low level in normal cells but can reach higher levels in cancer cells. It is the only membrane-bound collagenase and can also activate other MMPs, such as the soluble gelatinases MMP-2 and MMP-9 as well as the collagenolytic MMP-13.

7The TME contains numerous MMP substrates, including native fibrillar collagens and denatured gelatin as well as laminins. Stromal fibroblasts from MMP-14-deficient tumors do not degrade type I collagen, suggesting that cancer cell dissemination depends on TME remodeling by stromal cells. In addition to breaking down matrix barriers, MMPs can release antimetastatic cleavage products known as matrikines from ECM components of the primary tumor.

8MMPs and especially MMP-14 decisively influence the balance between cell adhesion and pericellular proteolysis of the ECM. For this purpose, the matrix receptors and proteases involved are interrelated in specialized adhesome structures called invadosomes. These are found in the form of invadopodia on cancer cells and in the form of podosomes on other cells, such as endothelial cells (ECs) during angiogenic sprouting. The pericellular proteolysis that these invadosomes cause and cell adhesion are two interdependent factors that determine the TME and, thus, ultimately the prognosis for cancer patients.

2. Cancer Progression Is Driven by MMPs in the TME

9Tumor progression and invasion of cancer cells are facilitated by numerous ECM remodeling and degrading enzymes. Among them are serine proteases, such as plasmin, plasmin activator, seprase, hepsin, and kallikreins; cysteine proteases, such as cathepsins B and K; aspartyl proteases, such as cathepsins D and E; metal ion-dependent proteases, such as MMPs and ADAMs; and others, such as heparanase, endoglycosidase, and hyaluronidase. Some of them can regulate each other’s activity, and activation cascades can include endogenous inhibitors, as in the case of MMP-2, which requires tissue inhibitor of metalloproteinase (TIMP)-2 to be activated by MMP-14. Moreover, activation cascades can also be intertwined, e.g., in cathepsin(s) that activate via uPA plasmin, which ultimately leads to MMP activation.

10More than other ECM-degrading enzymes, MMPs are pivotal in the TME. MMPs are involved in matrix disruption, neovascularization, and subsequent metastasis and are carefully controlled in a number of ways, e.g., by TIMPs. The function of the MMPs is not limited to the degradation of ECM molecules because some MMP substrates and cleavage products regulate cell growth, differentiation, and apoptosis, as well as chemotaxis, migration, and angiogenesis. Accordingly, the expression and activity of many MMPs correlate with tumor progression.

2.1. Epithelial-to-Mesenchymal Transition Depends on the Activity of MMPs

11By losing apical-basolateral cell polarity and intercellular adhesion and by acquiring a migratory and invasive phenotype typical of mesenchymal stem cells, carcinoma cells undergo EMT. Physiologically, it takes place during embryogenesis, wound healing, and fibrotic processes. Pathologically, it initiates cancer progression from a carcinoma in situ to an invasive tumor and metastasis. The concomitant morphological and phenotypic changes are associated with down-regulation of E-cadherin and an up-regulation of N-cadherin, fibronectin, and vimentin. The loss of tight junctions and adhesive connections in combination with an increased ECM-degrading MMP activity increases the cells’ ability to migrate and infiltrate, which is a fundamental requirement for metastasis. EMT appears to vary widely between tissue and cancer types. The transitions range from partial to full EMT, with carcinoma cells of intermediate EMT status being more prone to invasion and metastasis. While MMP-19 is a pure mesenchymal marker like the proteoglycan asporin, other MMPs are also significantly involved in EMT. MMPs with a demonstrated role in the EMT are MMPs -1, -2, -3, -7, -9, -14, and -28 (Table 1). MMP-14 induces a mesenchymal phenotype in cancer and development, by cleaving BM components as well as E-cadherin. MMP-14 and MMP-2 dynamically cooperate in regulating pericellular collagen homeostasis and cellular signaling processes.

2.2. The ECM-Degrading Activity of MMPs Is Involved in All Steps of the Metastasis Cascade

12In the next step of the metastatic cascade, cancer cells disseminate from the primary tumor to other tissues and organs. This is the most common cause of tumor morbidity and mortality. The invasion–metastasis cascade of hematogenous metastasis is a succession of local invasion, intravasation, survival in the circulation, arrest at a distant organ site, extravasation, initial survival in a foreign microenvironment and micrometastasis formation, and, ultimately, support by tumor angiogenesis, the formation of a secondary tumor. This process depends on cell motility and invasion, modulation of the microenvironment, plasticity, and colonization. In each of these steps, MMPs play a crucial role (Figure 1).

13Particularly, migration and invasion of cancer cells depend on the soluble MMPs -1, -3, -7, -9, -10, -11, -13, -26, and -28, and the membrane-type MMPs -14 and -16 (Table 1). Above all, MMP-14 is critical to the vascular metastatic route. Remarkably, low MMP-14 levels promote invasion and vascularization in vivo, while excessive ECM breakdown by MMP-14 counteracts cell migration and tumorigenesis.

2.3. ECM Remodeling by MMPs Is Important for Tumor Angiogenesis

14The vasculature provides the necessary blood supply to the tumor and facilitates the hematogenous dissemination of cancer cells. Over and above the co-option of preexisting blood vessels, tumors use all conceivable types of connection to the body’s blood circulation, with tumor angiogenesis being of particular importance. Several MMPs can be induced by angiogenic factors, such as VEGF, bFGF, TGF-α and -β, and angiogenin. The latter promote angiogenesis, vasculogenesis, lymphangiogenesis, and, in particular, tumor angiogenesis. In the TME, the angiogenic balance is precisely regulated by various MMPs. In particular, MMPs -1, -2, -3, -8, -9, -10, -11, -13, and -14 not only upregulate tumor angiogenesis but also can downregulate it depending on the prevailing conditions by releasing miscellaneous antiangiogenic ECM fragments or matrikines from the ECM during its remodeling (Table 1).

15Important for (tumor) angiogenesis, but not for vasculogenesis, MMP-14 acts as an endogenous suppressor in lymphangiogenesis by shedding LYVE-1 and inhibiting NF-κB-mediated VEGF-C production by macrophages. During angiogenesis, tip cells at the leading edge of the neovasculature transiently regulate matrix remodeling via MMP-14, while, in immature tumor vessels, MMP-14 expression is more diffuse. Moreover, MMP-14 may also shed VEGFR1 and semaphorin 4D, thereby reinforcing the proangiogenic signaling via VEGFR2 on ECs and stimulating CD8+ T-cell functions, respectively.

3.1. MMPs Show Many Structural and Functional Similarities and Yet Great Diversity

16MMPs are zinc- and calcium-dependent endopeptidases that can cleave all BM and ECM molecules. They belong, together with astacins, reprolysins, meprins, ADAMs, and ADAMTSs, to the metzincin superfamily. Of 28 MMPs occurring in vertebrates, 24 are found in humans, as MMP-23 comes in two isoforms encoded by different loci (MMP-23A and MMP-23B). According to their sequence similarity, domain organization and substrate specificity, they can be classified as (1) collagenases, (2) gelatinases, (3) stromelysins, (4) matrilysins, (5) transmembrane type I, (6) transmembrane type II, (7) glycosylphosphatidylinositol-anchored (GPI-anchored), and (8) other MMPs (Figure 2).

17Despite structural and functional differences, MMPs share a similar composition of individual domains. The generic structure of archetypal MMPs consists of an N-terminal signal peptide and a propeptide domain connected to a catalytic domain that is linked via a hinge region to a C-terminal hemopexin-like domain. However, matrilysins lack a hinge and a hemopexin-like domain, while gelatinases have a characteristic insertion of three fibronectin type II repeats within the catalytic domain. Furin-activatable MMPs typically contain a proprotein convertase RKRR recognition motif between their propeptide and catalytic domain. In contrast to soluble MMPs, membrane-anchored MMPs are bound to the plasma membrane via a transmembrane domain or via a glycosylphosphatidylinositol (GPI) anchor, whereas MMP 23 is a type II transmembrane protein. The transmembrane domain of membrane-bound MMPs is generally located near the C-terminus. MMP-23 is an exception as it is kept in its latent proMMP form not by a propeptide but by an N-terminal type II transmembrane domain that contains the sequence ALCLLPA instead of the consensus motif PRCGXPD.

18In the active center of all MMPs, three histidine residues in the HEXXHXXGXXH motif chelate a catalytically active zinc ion. Another zinc ion and two to three calcium ions stabilize the tertiary structure of the catalytic domain and largely determine the substrate specificity. Activation of proMMPs occurs via limited proteolysis by trypsin, other MMPs, plasmin, or furin-like convertases. Thus, a cysteine residue within the propeptide sequence PRCGXPD, or PRCGVTD for MMP-28, is removed and makes the catalytic center of the MMP accessible to the substrate. Alternatively, by oxidizing the thiol group, ROS may also render the oxidized thiol group incapable of complexing the active site Zn2+, thereby activating MMPs. Some MMPs are also activated allosterically by a substrate molecule binding to a so-called MMP exosite outside the catalytic domain. The membrane-bound MMPs -14 and -16 are activated by intracellular cleavage by furin. In addition, activation within the Golgi apparatus by the secreted proprotein convertase PCSK6 (PACE4) may occur. The other membrane-bound MMPs -15, -17, -24, and -25 also contain a furin cleavage site and are believed to be activated in a similar manner prior to their membrane association. Kallikrein-related peptidases can also proteolytically activate proMMPs.

3.2. MMPs Have Diverse Molecular Functions

19MMPs can cleave insoluble ECM components into soluble fragments. Proteolytically, they can activate or inactivate soluble proteins and can shed and release soluble ectodomains of membrane-bound proteins as autocrine or paracrine signals. MMP-14 shows the broadest substrate specificity of all membrane-bound MMPs, especially towards components of the pericellular ECM. While MMP-14 can cleave the interstitial collagen types I, II, and III. Although MMP-14 cannot directly break down type IV collagen, it can activate MMP-2 to break it down, especially during the growth of carcinomas. The other membrane-bound MMPs -15, -16, and -17 can also activate pericellular proMMP-2. MMP-15 also cleaves type I collagen, albeit with a 100-fold lower specific activity than MMP-14, whereas MMP-16 cannot cleave type I collagen but type III. Invasion of fibrin matrices is promoted by the fibrinolytic activity of MMPs -14, -15, and -16. Shedding of N-cadherin by MMP-17 weakens intercellular contacts and supports EMT.

20In addition, the pericellular environment contains numerous other molecules that can be processed by MMPs (Table 1). Among these are protease inhibitors, such as α1-anti-chymotrypsin, α1-proteinase inhibitor, α2-macroglobulin, PAI (plasminogen activator inhibitor)-1, plasmin C1-inhibitor, and serine proteinase inhibitor-E2 (SERPINE2). Additionally, many cytokines, such as pro-IL-1β, pro-IL-8, CXCL5, CXCL9, CXCL10, CXCL11 precursor, and CXCL11, CXCL12 (SDF), pro-TNF-α, and growth factors like pro-TGF-β as well as numerous other non-matrix molecules are susceptible to cleavage by MMPs.

21Even several intracellular proteins, such as cytoskeletal proteins, nuclear lamins, chaperones, regulators of transcription, translation, and apoptosis, which are involved in, e.g., transcription, translation, and carbohydrate metabolism, are reportedly MMP substrates. The intracellular MMP-14 substrates that have been confirmed or identified with high confidence by degradomics include, in particular, cytoskeletal proteins, such as α-actinins -1 and -4, actin regulatory protein CAP-G (capping actin protein, gelsolin-like), actin-related protein (Arp)-2, cofilin-1, ezrin, filamins -A, -B and -C, gelsolin, moesin, plectin-1, profiling-1, tubulin-α/β, and vimentin, along with glycolytic enzymes. While MMP-14 degrades the ECM scaffold extracellularly, this proteolytic cleavage of focal adhesion kinase (FAK) and signaling molecules by MMP-14 additionally promotes the disengaging of focal adhesions and thereby further enhances cell motility and thus the invasion of cancer cells.

22Independently of its proteolytic activity, MMP-14 can also promote cell migration with its cytoplasmic domain. After phosphorylation of its cytoplasmic domain, MMP-14 regulates Rac1 signaling in developing osteoclasts via p130Cas. It also interacts with the late endosomal/lysosomal adaptor, MAPK, and mTOR activator 1 (LAMTOR1, p27RF-Rho) and, via the activation of RhoA, it promotes RhoA-dependent actin polymerization and thus cell invasion.

3.3. Matrix Metalloproteinases Are Tightly Regulated

23The various MMPs must be stringently regulated to fulfill their functions in different processes without causing accidental proteolysis. While MMP expression is usually carefully regulated from the transcriptional to the post-translational level, in order to narrowly limit its spatio-temporal distribution and activity, this regulation is lost in many cancers. Although MMP-mediated ECM remodeling and degradation play a central role in metastasis, their genes are usually not amplified, but rather dysregulated.

24The proteolytic activity of MMPs is regulated on four levels: (1) regulation of gene expression by epigenetic and transcriptional control mechanisms as well as by mRNA stability, (2) compartmentalization in vesicles and membrane micro-domains in the case of membrane-bound MMPs, (3) activation from an inactive zymogen-form, and (4) inhibition of proteolysis.

25MMP gene expression is carefully regulated via, for example, NF-κB, MAPK, and JAK/STAT signaling by cell–matrix and cell–cell interactions as well as by growth factors, glucocorticoids, cytokines, retinoic acid, interleukins, and eicosanoids. Some MMP promoters are co-regulated due to common regulatory motifs and structural properties. In addition to classifying the MMPs according to their substrate specificity, it is, hence, possible to classify them into three groups according to the regulation of their gene expression. The largest group is formed by the MMPs -1, -3, -7, -9, -12, -13, -19, and -26, the promoters of which all have a TATA box (Goldberg Hogness Box) and an AP1 site, while the promoters of the second group, consisting of MMPs -8, -11, and -21, have a TATA box but no AP1 site. The MMPs- 2, -14, and -28, forming the third group, lack both, which is why they are rather constitutively expressed but are excessively expressed in some diseases. The EGF receptor (EGFR) that is constitutively activated in many cancers can simultaneously activate many MMP genes as well as other genes. In mesenchymal and monocytic cells, inflammatory signals like the cytokines IL-1β, TNF-α, oncostatin M, RANKL, and microbial lipopolysaccharide (LPS) are the strongest transcription activators of MMPs -1, -3, -9, -13, and -14. The expression of MMPs -2, -14, and -28 is less responsive to cytokines and growth factors than that of other MMPs. Of all 23 human MMP genes, only those of MMPs -9, -14, and -15 respond to the transcription factor E2F, although all have a corresponding binding site.

26Post-transcriptionally, trans-acting RNA-binding proteins and microRNAs regulate the synthesis of MMPs via their mRNA stability. For example, MMP-14 can be downregulated by miR-181a-5p, thus inhibiting cancer cell migration and angiogenesis. Similarly, miR-7 downregulates MMP-14. Furthermore, long non-coding LncRNAs regulate MMP expression. For example, the bladder cancer-associated transcript-1 (BLACAT1) downregulates the expression of MMPs -2, -9, and -14 by interacting with miR-142-5p. MMPs are also subject to regulation by circular RNAs, such as circ_0007843, which binds to miR-518c-5p and upregulates MMP-2 by canceling the inhibitory effect of the miRNA.

27At the co- and post-translational levels, other regulation options are synthesis and degradation, partial proteolysis and activation by furin, phosphorylation, glycosylation, and interaction with other intracellular and extracellular proteins and lipids. MMPs can mutually activate or inactivate each other in a complex network (Figure 3, Table 1). For example, MMP-14 can inactivate MMP-11 in the pericellular space irreversibly by proteolytic cleavage of its catalytic domain or reversibly via TIMP-mediated inhibition. There is also the possibility of proteolytic autoregulation, e.g., autocatalytic shedding terminates the MMP-14 activity on the cell surface, whereas non-autocatalytic shedding can release soluble, active MMP-14 ectodomains that are able to bind TIMP-2, thus creating a finely balanced equilibrium of soluble active and inactive enzyme fragments.

28The proteolytic activity of MMPs, like that of ADAMs and ADAMTSs, is tightly controlled by the tissue inhibitors of metalloproteinases (TIMPs). These form 1:1 stoichiometric complexes with MMPs, with the N-terminal domain of the TIMP chelating the catalytic zinc ion in the active center of the MMP and thereby inactivating it. In contrast, TIMPs can also interact with their C-terminal domain with the hemopexin domain of MMPs and thereby activate them.

29In particular, TIMP-1 can activate MMP-9 by forming a ternary complex of proMMP-9 with MMP-3 and TIMP-1. Likewise, TIMP-2 participates in the activation of MMP-2 by forming a complex with proMMP-2 and MMP-14. This latter mechanism also illustrates the central importance of MMP-14 as the master MMP in particular in invadopodia of invading cancer cells: Two MMP-14 molecules dimerize on the plasma membrane, with the catalytic center of one MMP-14 binding the N-terminal domain of a TIMP-2, which can interact with its C-terminus with the hemopexin domain of proMMP-2. This positions proMMP-2 so that the other MMP-14 can cleave it and release the active MMP-2. Its transmembrane domain, but not its hemopexin domain, mediates the necessary MMP-14 homodimerization. In contrast, the activation of MMP-13 by MMP-14 takes place independently of TIMP-2 but depends on the hemopexin domain of MMP-13.

30MMP-14 is strictly regulated, starting with the level of transcription through post-translational modifications to its compartmentalization. MMP-14 gene expression is epigenetically regulated by histone modification, chromatin remodeling, and DNA methylation-sensitive transcription factors such as SP1. The methylation status of the MMP-14 promoter, like that of the MMP-2 promoter, correlates inversely with gene expression and cell migration in vitro, with hypomethylation of the promoter and of histone H3 being associated with high levels of expression of MMP-14 and MMP-2, respectively.

31At the transcription level, MMP-14 is also subject to strict and differential regulation with at least five transcription start sites. Unlike the promoters of other MMP genes, the MMP-14 promoter lacks a TATA box and an AP1 binding site. It markedly responds to SP1 and numerous other activating transcription factors such as hypoxia-inducible factor (HIF)-2α and EGR-1, as well as E2F1, -3, and -5, and SNAI1, all of which are associated with increased malignancy in the context of various cancers. SNAI1 stands out among these because it critically regulates EMT by down-regulating E-cadherin. SP1 is responsible for v-Src-induced upregulation of MMP-14. The MMP-14 promoter also has a binding site for the repressing transcription factor PROX1 upstream of the main transcription start site, which significantly affects the invasiveness of cancer cells by downregulating MMP-14.

32In particular, ECM biomechanics and dimensionality affect MMP-14 expression. Mediated by α2β1 integrin, collagen contact and mechanical forces in the TME cause an increase in the expression of MMP-14 via the transcription factor EGR-1. At the protein level, MMP-14 is activated by the enzymatic removal of its N-terminal propeptide by the proprotein convertase furin. This is mediated by Golgi reassembly stacking protein 55 (GRASP55) serving as adapter while passing the trans-Golgi compartment, so that MMP-14 reaches the cell surface as an active enzyme.

33In contrast to MMPs -1, -2, -3, and -9, whose upregulation in hypoxia is controlled by HIF-1α, MMP-14 lacks a HIF-1α binding site in its promoter. Instead, MMP-14 is upregulated under the hypoxic conditions of the TME by EGR-1 and HIF-2α. Hypoxia also induces translocation of MMP-14 to invadopodia via the small GTPase RhoA. Another notably non-proteolytic feature of MMP-14, relevant in a hypoxic TME, is its ability to promote the expression of HIF target genes and the Warburg effect by activating HIFs via Munc18-1-interacting protein 3 (Mint3) and factor inhibiting HIF-1 (FIH-1). Under the hypoxic conditions of TME and depending on the increase in HIF-1α, MMP-15 as well as MMP-9 are simultaneously expressed increasingly.

34MMP-14 is packaged in intracellular vesicles attached to microtubules via motor proteins. From this storage compartment, MMP-14 is delivered to developing invadopodia with the help of nesprin-2 and the dynein adaptor Lis1. Motor proteins of the kinesin superfamily (KIFs) transport the MMP-14-containing vesicles along microtubules to the cell surface. This transport is bidirectional and depends on the respective KIF. For example, KIF1B brings MMP-14 to the cell surface. In MDA-MB 231 breast cancer cells, the transport of vesicles with MMP-14 to the cell surface is triggered by the binding of β1 integrins to collagen in a Rab8-GTPase-dependent manner. Via integrin-mediated cell–matrix contacts, MMP-14-containing vesicles are directed to invadopodia at the cancer cell’s invasive front for local pericellular ECM proteolysis. Securely stored in intracellular vesicles, activated MMP-14 can be quickly released to the cell surface when required. Contact with MMP-14-containing endosomes is mediated by the endoplasmic reticulum protein protrudin, and the Rab7-binding kinesin adapter protein FYCO1 expedites them to the plasma membrane of outgrowing invadopodia. In addition, the endosomal trafficking of MMP-14 is regulated by the intracellular chloride channel 4 (CLIC4), which binds to the endosomal sorting complex (ESCRT) required for transport and also to proMMP-14, thereby promoting its proteolytic activation in lipid rafts. Recycling of MMP-14 to sites of invadopodia formation is also regulated by β1 integrin-mediated Src-EGFR signaling and MMP-14 phosphorylation. As fibroblasts migrate through dense collagen, MMP-14 is activated and kept at the cell surface by association with collagen-binding β1 integrins, particularly α2β1 integrin, which brings collagen to MMP-14 for proteolytic cleavage. However, the regulation of the expression and activity of MMP-14 by collagen-binding integrins and how the topography and biomechanical properties of supramolecular collagen affect MMP-14-dependent cancer cell invasion are still not completely understood. According to the polarity of epithelial cells, MMP-14 is normally only transported to their apical surface and not to their basolateral side. Stimulation with HGF, however, induces a partial translocation of MMP-14 to the basolateral side, which allows matrix remodeling and outgrowth of epithelial tubular structures into the ECM.

35On the cell surface, MMP-14 activity is regulated by endogenous inhibitors such as TIMPs, RECK (reversion-inducing, cysteine-rich protein with Kazal motifs), testican-3, and N-Tes. In particular, TIMP-3 as a guardian of the ECM regulates MMP-14, while TIMP-2 rather is involved in MMP-14-mediated activation of proMMP-2. The exposure of MMP-14 on the cell surface, but not MMP-14 gene transcription, is dependent on ADAM12, which forms with αvβ3 integrin and MMP-14 a matrix-degrading ternary complex. However, the proteolytic activity of ADAM12 is not necessary for the regulation of MMP-14 activity.

36The collagenolytic activity of MMP-14 on the cell surface is enhanced predominantly by its hemopexin domain-dependent homodimerization. It is regulated by interactions with integrins, CD44, chondroitin/heparin sulfate proteoglycans, tetraspanins, pericellular MMP-14-inhibiting proteins TIMP-2, -3, and -4, and RECK. The O-glycosylation pattern also determines the lifespan of MMP-14 and, thus, the invasiveness of cancer cells. The amount of MMP-14 on the cell surface is regulated by clathrin- or caveolin-mediated endocytosis and its half-life on the cell surface is less than 30 min. Clathrin- and caveolin-dependent internalization and recycling of MMP-14 in response to integrin-mediated matrix adhesion is controlled via FAK- and Src-mediated phosphorylation of caveolin-1 and the cytoplasmic tail of MMP-14. For clathrin-dependent endocytosis, the cytoplasmic domain of MMP-14 interacts with the coat assembly protein AP-2µ2, a component of clathrin-coated pits. An important post-translational modification that regulates clathrin-dependent endocytosis of MMP-14 and, thus, MMP-14-dependent cell migration is a palmitoylation of its cytoplasmic domain close to its C-terminus. Caveolin-1 antagonistically reduces the amount of MMP-14 on the cell surface by flotillin- and Rab5-dependent internalization. VEGFR 2 can activate Src in ECs, and phosphorylation of caveolin-1 by Src induces the interaction of caveolin-1 with the cytoplasmic tail of MMP-14 leading to endocytosis of MMP-14. In addition to its palmitoylation, the endocytosis of MMP-14 is regulated by protein kinase C (PKC)-mediated phosphorylation of its cytoplasmic tail and promoted by the membrane-bending protein endophilin. Internalized MMP-14 is subsequently degraded or recycled to the cell surface. In order to get back to the cell surface after endocytosis, its C-terminal sequence DKV582 is essential. Notably, after dissolution of podosomes, MMP-14 that remains in small membrane islets can seed the reemergence of new podosomes at these sites. Another means of down-regulating the MMP-14 activity on the cell surface is its autoproteolytic or MMP-2-mediated cleavage of its catalytic domain.

37The MMP-14 ectodomain can be shed autocatalytically and non-autocatalytically from the cell surface, either generating catalytically inactive fragments or releasing soluble, catalytically active ectodomains. Nevertheless, membrane localization is a prerequisite for invasiveness because a recombinant, soluble MMP-14 does not promote cellular invasion.

3.4. MMP-14 Has a Central Role among the MMPs

38As the master MMP, MMP-14 is widely expressed on many cells and is particularly overexpressed on malignant cancer cells and correlates with poor prognosis. MMP-14 is essential for pericellular collagenolysis and remodeling of tumor stroma. This is a direct consequence of its involvement in the cleavage of BM and stromal ECM components, the activation of other MMPs, the release of bioactive molecules, such as TGF-β, SDF, cytokines, and matrikines, the cleavage of cell–cell and cell–matrix adhesion molecules, and other non-proteolytic functions in cancer progression. Because of its numerous functions, MMP-14 is vital for normal development. Its absence results in perinatal lethality. In cells, MMP-14 knockout results in senescence, which, however, can be avoided with retinoic acid.

39MMP-14 (Figure 4) is a membrane-bound endopeptidase that has various pericellular activities. Through the MMP-mediated cleavage of ECM components, biologically active molecules such as growth factors and cytokines including TGF-β are released or modified. Further MMP-14 substrates are latent TGF-β-binding protein 1 and pro-TGF-β as well as soluble chemokines such as the stroma cell-derived factor (SDF)-1 and the monocyte chemoattractant protein (MCP)-3. The proteolysis of collagens and other components of the pericellular ECM in the TME activates cell signaling pathways by means of the MMP-14-generated fragments and, thus, enables cell invasion of the ECM. Moreover, MMP-14 on the cell surface can bind ligands that cause structural changes in it and affect its interactions with other cell surface molecules as well as intracellular signaling via its cytoplasmic tail.

40The fibril-forming collagen types I, II, and III, in particular, and other ECM proteins such as fibronectin, vitronectin, fibrinogen and fibrin, nidogen, BM laminins, and laminin-332, which is ectopically expressed in the tumor stroma, are substrates of MMP-14. MMP-14 can also activate MMPs -2, -8, and -13. MMP-14 is the enzyme that determines the rate of collagen turnover, although other proteases including MMPs -1, -2, -8, and -13 as well as cathepsins B, K, and L can also cleave the fibrillar type I and III collagens.

41Among the cell surface-bound MMPs, MMP-14 is the only one with collagenase activity. While MMP-14 is physiologically expressed on different cell types, e.g., ECs and adipocytes, it is essential especially for cancer cells. Here, its expression serves as an important prognostic marker, e.g., in breast cancer, as it correlates with metastatic potential. In cancer progression, as in physiological developmental processes, a deficiency in MMP-14 cannot be compensated for by other MMPs. A complete knockout of MMP-14 in mice causes delayed ossification, decreased angiogenesis, severe fibrosis, and early mortality. MMP-14 knockdown by means of either RNA silencing or proteolytic shedding of the MMP-14 ectodomain diminishes cancer cell invasion. In contrast, in a collagen-rich environment, the invasion of cancer cells is increased by overexpression of MMP-14. Within the TME, cancer-associated fibroblasts (CAFs) also express MMP-14 and thereby contribute to invasion and metastasis, as shown in a murine breast cancer model.

42The HPX domain of MMP-14 plays an important role in the binding and subsequent cleavage of collagens since collagen can bind unobstructedly when blade IV associates with the lipid membrane. In addition, the interaction of the HPX domain with a lipid bilayer via its blades II and IV exposes a binding site that mediates heterodimerization with the hyaluronan receptor CD44. This, together with the observation that lipid vesicles promote the cleavage of collagen by MMP-14 ectodomains, suggests a side-by-side homodimerization of MMP-14, allowing binding to lipid bilayers, collagen, and CD44, as well as oligomerization.

43Membrane-bound cell and matrix receptors, such as E-cadherin and CDCP1 cadherin, syndecans -1 and -2, and the hyaluronan receptor CD44 can also be cleaved by MMP-14.

44MMP-14 also increases cancer invasiveness by cleaving the N-terminal heparin-binding domain of heparin-binding EGF-like growth factor (HB-EGF) to convert it into a heparin-independent growth factor. Ectodomain shedding of HB-EGF is also possible by ADAMs. However, forming a complex with FGFR2 and ADAM 9 on the cell surface, MMP-14 can also cleave and inactivate ADAM9 and, thus, protect against FGFR2 shedding.

45By shedding the hyaluronan receptor CD44 from the cell surface, MMP-14 and ADAMs, such as ADAM-10 and -17, can promote cell migration and invasion. By shedding syndecan-1 or by proteolytically activating αv integrins, MMP-14 also increases cell migration.

46Furthermore, MMP-14 is involved in the reorganization of the actin cytoskeleton through cleavage and shedding of the receptor protein tyrosine kinase PTK7, which is essential to the Wnt/planar cell polarity pathway and, hence, relevant for EMT.

47Still a conundrum is the presence and catalytic activity of MMP-14 within the cytoplasm and nucleus. Several intracellular and intranuclear substrates and interaction partners have been reported for MMP-14, such as pericentrin, a component of chromosomal centrosomes, centrosomal BRCA2, a DNA repair-associated tumor suppressor, the cytoskeletal proteins ezrin and moesin, and glycolytic enzymes. MMP-14 can transcriptionally downregulate the mRNA levels of Dickkopf-related protein-3 (DKK3) in urothelial carcinoma cells, which is secreted and regulates cell invasion by interaction with Wnt signaling. Furthermore, nuclear MMP-14 can stimulate the expression of SMAD1 via TGF-β signaling. In the nucleus of a macrophage, MMP-14 may serve non-proteolytically as an epigenetic regulatory element and as a transcription factor of pro-inflammatory gene expression in macrophages.

48MMP-14 is especially carefully regulated (Figure 5) because it by itself affects so many other proteins with structural, signaling, enzymatic, and non-enzymatic functions. MMP-14 is upregulated in cells by various substances such as phorbol ester or concanavalin-A and, in particular, by a three-dimensional collagenous microenvironment. In contrast, the regulation of MMP-14 by tumor necrosis factor-α (TNF-α) is still unsettled. MMP-14 is also upregulated by EMT-specific transcription factors such as SNAI1, TWIST, and ZEB. SNAI1 also induces MMP-14- and MMP-15-dependent BM transmigration by cancer cells.

4. Cellular Adhesome Structures in the TME

49Integrins can perceive mechanical forces via cryptic binding sites on ECM molecules, which are made accessible by mechanical forces after being exposed through proteolytic activity, e.g., through MMPs. Thus, pericellular proteolysis by MMPs, cell adhesion, and migration are interdependent processes, in which various adhesome structures are involved. The (dys)balance between adhesion to and proteolysis of the ECM by cancer and stromal cells strongly affects cancer progression. The protein interactome of adhesomes has been meticulously elucidated. Pertinent features of the most prevalent non-proteolytic and proteolytic adhesome structures (Figure 6) are summarized in Table 2.

4.1. Using Varied Adhesome Structures, Cells Can Interact Differently with the ECM

50Dysregulation of normal cell growth in cancer does not only affect cancer cells but also stromal cells. Cell growth and migration depend inter alia on the interaction of these cells with the ECM, mediated by adhesion receptors and other adhesome components. Cell adhesion is mediated via integrins. They reinforce the connection of the ECM to the cytoskeleton. However, their role depends on the type and stage of cancer. They are composed of 18 α and 8 β subunits in mammals that form 24 different heterodimers. These heterodimers bind to a variety of ligands, which are divided into Arg-Gly-Asp (RGD) binding and non-RGD binding receptors. Integrins are characterized for having three different conformational changes. Inactive integrins with low affinity for the ECM ligand adopt a bent-closed conformation, whereas active integrins, capable of binding ligands with increasing affinity, adopt an extended-closed and extended-open conformation. These conformations depend on activators, inactivators, and ligand interactions of the integrins.

51Signaling via integrins is bidirectional: inside-out and outside-in signaling. In inside-out signaling, intracellular integrin activators, e.g., talin and kindlin, induce integrin activation by binding to the integrin β subunit tail. In outside-in signaling, signals originate from ECM ligand binding to the integrin extracellular domain and are conformationally conveyed to the cytoplasmic domain. Thus, mechanical signals in the cell could be transduced via conformational changes either outside-in or inside-out. These signals regulate cell migration, differentiation, proliferation, survival, and cytoskeletal organization.

52The adhesome comprises the entire network of structural and signal proteins that are involved in the regulation of cell–matrix adhesion. While several hundred different proteins occur in various adhesome structures, the core adhesome centered around the integrin consists of around 60 proteins that are common to all adhesome structures. Among them are tyrosine and serine/threonine kinases, phosphatases, guanine nucleotide exchange factors, GTPase activating proteins, E3-ligases, and proteases that regulate adhesion through post translational modifications of many of its structural and scaffolding proteins. Varying in size, shape, distribution, dynamics, and molecular components, adhesome structures show plasticity and enable cells to perceive, adapt, and respond to differences in the extracellular environment. According to morphological and molecular criteria, adhesome structures can be divided into focal complexes, focal adhesions, and fibrillar adhesions, with their corresponding correlates in three-dimensional matrices, as well as invadosomes. They also have different functions. Some predominantly serve mechanical anchorage of cells, while others possess proteolytic activities. It is important to understand when and how a cell switches its adhesome type, e.g., from focal adhesions to invadosomes. Moreover, albeit having ECM-cleaving activity, invadopodia protruding into the ECM can expand matrix defects and cavities by means of contractile forces without using proteases.

4.2. Focal Complexes Are Formed as the First Adhesive Matrix Contacts

53Cells form different membrane protrusions to explore the surrounding ECM, such as filopodia and lamellipodia. MMP-14 has been reported to be also localized to filopodia and lamellipodia, where it indirectly associates with the actin cytoskeleton by binding with its HPX domain to the hyaluronan receptor CD44. These membrane protrusions are mechanically stabilized by adhesive matrix contacts, to which several adhesome components are recruited, e.g., regulators of lamellipodial cell migration, Rac, WASp, Arp2/3, arpin, lamellipodin, WAVE, Mena, and Ena/VASP family members. They also control actin dynamics in both endocytosis processes and invadopodia. Upon initial integrin-mediated contact to the ECM, more integrins can be recruited to the contact site, forming a nascent cell adhesion contact or focal complex. Such focal complexes, developing from nascent focal complexes with a diameter of 0.25 µm and a half-life around 60 s, can mature into larger and more stable focal adhesions and further into fibrillar adhesions.

4.3. Focal Adhesions and Fibrillary Adhesions Allow Force Exertion

54Cells migrating on a two-dimensional surface form lamellipodia, in which initially formed focal complexes are converted into focal adhesions for force transmission. Therefore, lamellipodia can be considered as the engine that propels a migrating cell. In addition, proteases, such as MMP-14, MMP-2, uPA(-R), and seprase, can localize in lamellipodia with structures containing integrins or paxillin that, thus, are distinct from focal complexes or adhesions. Mechanosensors such as actin polymerization-inducing Ena/VASP-like (EVL) promote durotaxis and reinforce focal adhesions. MMP-14 can be recruited to focal adhesions due to the association of its cytoplasmic domain with a FAK-p130Cas complex. However, the cytoplasmic domain of MMP-14 is dispensable for the degradation of the underlying matrix and localization at focal adhesion sites. In contrast, a so-called MT-loop of eight amino acids in the catalytic domain of MMP-14 is critical for its localization at focal adhesions when the ECM is degraded there.

55Focal adhesions can grow into fibrillar adhesions, which are involved in ECM remodeling, especially in fibroblasts adhering to a fibronectin matrix. Moreover, tumor cells tend to realign the meshwork of collagen fibers in the ECM of the TME by forming fibrillary adhesions.

4.4. Podosomes Coordinate Cell Adhesion with Focal ECM Degradation

56At the ventral side of the Ras-transformed fibroblasts, vinculin and α-actinin can rearrange from focal adhesions into circular membrane protrusions, which, on the one hand, mediate cell adhesion and were, therefore, referred to as podosomes, and, on the other hand, proteolytically degrade the ECM, which is why the term invadopodia was coined soon afterwards. It is controversial whether podosomes majorly differ from cancer cell invadopodia and/or whether invadopodia are merely dysregulated podosomes. Therefore, both are grouped under the generic term invadosomes.

57Podosomes are conical, actin-rich structures on the surface of normal non-cancerous cells that serve both cell–matrix adhesion and localized ECM degradation. They are usually between 0.5 µm and 2.0 µm in diameter and length. With a lifespan of just a few minutes, they are more dynamic than invadopodia. While invadopodia are characteristic of invading cancer cells, podosomes are involved in normal biological processes such as overcoming tissue barriers by immune cells or in bone remodeling. Hence, podosomes are found on macrophages, dendritic cells, and osteoclasts, but also on ECs, vascular smooth muscle cells, and Src-transformed fibroblasts. Podosomes as well as similar structures in Ras-transformed fibroblasts, ECs, macrophages, and dendritic cells contain MMP-14. If, despite having specific characteristics of podosomes, the adhesome structure deviates from the consensus, it is sometimes referred to as a podosome-like structure.

58Podosomes coordinate the degradation of the ECM with cell movement and, thus, regulate migration in the microenvironment, which is crucial for processes such as embryonic development, wound healing, and inflammatory reactions. Podosomes are also involved in mobilizing mesodermal progenitor cells (MPCs) in the bone marrow that differentiate into endothelial or mesenchymal cells. As a multi-purpose organelle, podosomes are additionally involved in weakening tight junctions of ECs by sequestering zonula occludens’ proteins and in the fusion of cells, such as osteoclasts, myoblasts, and macrophages.

59The turnover of the podosomal actin core, which is carefully regulated by Arp2/3, WASp, cortactin, and numerous other actin nucleators, polymerization activators, actin-binding, and cross-linking and scaffolding proteins as well as kinases and small G proteins, takes seconds. Confined by a cap structure, from the dense actin core, a set of unbranched filaments protrudes radially towards a ring of adhesion plaque proteins, such as paxillin, vinculin, talin, and integrins, as well as p21-activated kinase 4 (PAK4), while others extend to neighboring podosomes. In the ring complex, integrins and integrin-associated adhesion plaque proteins connect the cytoskeleton to the ECM. The cap essentially regulates podosome contractility. A detailed explanation of the podosome architecture and mechanics can be found in.

60The formation of podosomes depends not only on the structure and composition of the underlying substrate and the presence and distribution of specific integrin ligands, but podosomes also act as mechanosensors. A higher matrix stiffness extends the lifespan of podosomes and results in a closer spacing between them. With their integrin-containing ring structure, podosomes generate mechanical forces in the range of several pN.

61The major cellular transducer of mechanical signals in a cell is YAP, which responds to a broad range of signals, such as shear stress, cell shape, and ECM rigidity. Through ECM remodeling, MMP-14 can promote integrin clustering that activates a β1-integrin/Rho GTPase signal cascade, which leads to the nuclear translocation of the transcription coactivators YAP and TAZ. In addition, YAP signaling is controlled via its ubiquitination and subsequent degradation by the ubiquitin domain-containing protein 1 (UBTD1), associated with β-catenin at cell–cell adhesion sites.

4.5. Invadosomes Are Both Adhesive and Proteolytic Structures

62The umbrella term invadosomes combines the adhesome structures, invadopodia and podosomes, both of which allow the focal breakdown of ECM. According to an updated definition proposed by Cambi and Chavrier, a mesoscale organization for podosomes and the location underneath the nucleus for invadopodia are important criteria for classification, in addition to minimal structural requirements, such as the incorporation of cortactin and a core of F-actin, as well as the ability to degrade the ECM.

63Invadopodia (Figure 7) have an actin core surrounded by actin-binding proteins, scaffold proteins, and adhesion molecules. They are formed in three successive steps, starting from initiation, through stabilization to maturation. Invadopodia formation is largely initiated via PI3K by Src family kinases after activation by EGF, TGF-β, or PDGF, whereupon plasma membrane buds are formed. In contrast to focal adhesion-mediated cell–matrix interaction, which is associated with myosin-II-mediated cell functions, an increase in Src activity shifts the cellular adhesome towards the formation of invadosomes. The Src kinases then phosphorylate invadopodia proteins, such as TKS5, synaptojanin-2, and tyrosine-protein kinase ABL2 (Arg). Through their phosphorylation, N-WASp is recruited to invadopodia, which, by means of Arp2/3, promotes actin polymerization and, thus, invadopodia elongation. Subsequently, the scaffold protein TKS5 interacts with its phox homology (PX) domain with the phospholipid PI(3,4)P2, whereby the invadopodium core is anchored to the plasma membrane and the newly formed invadopodium is stabilized. A sustained actin polymerization, regulated by cofilin, fascin, tyrosine-protein kinase ABL2, and mDia2, together with the recruitment of MMP-14 as well as MMP-2 and MMP-9, results in mature invadopodia, in which an actin core is surrounded by a ring of adhesion proteins, such as integrins, paxillin, vinculin, a-actinin, and HIC-5 (TGFB1I1). Their lifetime and the spatiotemporal secretion of MMPs is controlled by Rho GTPases.

64By the regulation of this intracellular trafficking, activated MMP-14 is kept ready in intracellular vesicles clustered around the centrosome and close to the cell nucleus for ‘digest on demand’. MMP-14 is targeted to the base of invadopodia by means of late endosomes and lysosomes. Fusion of MMP-14-bearing vesicles is mediated via synaptotagmin VII. Instead of vesicles, endosomal tubules can form in a JIP3/4- and WASH-dependent manner to deliver MMP-14 to the tip of invadopodia.

65β1 integrin signaling is crucial for the formation of invadopodia in various cancer cell types. Recycling of MMP-14 at invadopodia formation sites is controlled by the phosphorylation of MMP-14 via the β1-integrin-Src-EGFR signaling pathway. β1 integrins control SNARE-dependent delivery of Src and EGFR to sites of invadopodia formation. Additionally, lamellipodia formation and membrane ruffling, as well as focal adhesion kinase signaling and Src-regulated focal adhesion turnover, depend on SNARE-mediated membrane traffic. Likewise, the exposure of MMP-14 on the surface of invadopodia depends on SNARE complexes containing SNAP23, VAMP3, syntaxin13 or SNAP23, syntaxin4, and VAMP7. Additionally, MMP-14 can be delivered into the pericellular ECM by means of exosomes, which are released by fusion of late multivesicular endosomes with the plasma membrane. Active MMP-14- and β1-integrin-containing exosomes can activate proMMP-2 and promote ECM degradation. Thus, SNARE regulators may be targets for the development of antimetastatic therapies for cancers with invadopodia involvement.

66TKS5, integrin, F-actin, cortactin, and MMP-14 were identified as prognostic markers related to invadopodia and their targeting curbs breast cancer metastasis. The scaffold protein TKS5 correlates with invasiveness. Its overexpression, e.g., in prostate cancer, promotes the formation of invadopodia and matrix degradation in a Src-dependent manner. Additionally, in gliomas, increased TKS5 expression correlates with poor patient prognosis. In a mouse model of lung adenocarcinoma, non-metastatic tumors expressing a short isoform of TKS5 could be turned into invasive ones by the expression of a long TKS5 isoform found in invasive tumors. Conversely, the knockdown of TKS5 in human mammary epithelial (HMLER) cells decreases tumor invasion and metastasis.

67Cortactin is concentrated in invadopodia of head and neck as well as breast cancer cells. For instance, microinjections of anti-cortactin antibodies reduce the ECM degradation at invadopodia in MDA-MB-231 cells. On the other hand, an increase in the ECM degradation and invadopodia number occurs after cortactin overexpression of HNSCCs and MDA-MB-231. Cortactin and TKS5 associate and correlate in their expression with different proteases, which are related to invadopodia, including MMP-2, MMP-9, and MMP-14. The exact mechanisms of how the cortactin and TKS5 regulate the MMPs’ secretion are still unknown.

68Invadopodia are highly dynamic structures. Nevertheless, they have a longer half-life than podosomes. Ras GTPase-activating-like protein (IQGAP1) can control the lifespan of invadopodia by keeping Cdc42, which plays a crucial role in the formation of invadopodia, active. With a length of more than 2 µm and a width between 0.5 µm and 2 µm, they are also larger than podosomes. Accordingly, invadopodia penetrate deeper into the ECM than podosomes and degrade the ECM to a greater extent. Invadopodia persists for many hours, whereas podosomes have a life span of a few minutes. The number of invadopodia and podosomes depends on the cell type. Nonetheless, it has been reported that there are around seven invadopodia and up to hundreds of podosomes per cell. Invadopodia are preferably formed under the cell nucleus, which serves as a mechanical abutment to increase their propulsive power (Figure 7). Investigating the role of focal adhesions in invadopodia stability, so-called focal adhesion rings containing vinculin and talin were found to oscillate just like cortactin with a period of 10 min, demonstrating that invadopodia are highly dynamic structures in which ECM adhesion and proteolysis are finely tuned. For this purpose, invadopodia as well as podosomes serve as local storage depots for proteases near and at the cell surface.

69It must be noted that the general invadosome ring model needs to be studied further using three-dimensional fluorescence microscopy. A ring organization is not mandatory for the constitution of the core. In fact, invadosomes can be organized into six different clusters depending on the cell type: linear, array, single, rosette, belt, and ring. This is the case, e.g., in trophoblast podosomes, which form an atypical core.

70Invadopodia are the equivalent of podosomes on malignant cells. They are equipped with proteases that can break down the pericellular ECM. Although the serine protease seprase was originally identified as invadopodia-localized protease, the major protease responsible for ECM degradation by invadopodia is MMP-14. The localization of MMP-14 in invadopodia depends on its cytoplasmic domain, which is also necessary for the N-WASp-mediated localization of MMP-14 in invadopodia-like structures. Other major constituents of invadopodia are, in addition to β1 and β3 integrins, an F-actin scaffold; cytoskeletal regulators, such as cortactin, fascin, Arp2/3, cofilin, WASp family members, Mena/VASP, paxillin, and Rho family GTPases; and the scaffold and adaptor proteins NCK1 and TKS4/5, as well as various kinases, such as Src, ABL kinases, PKC, FAK, PTK2B, and PI3K.

71Invadosomes also have a dynamic life cycle. Cells of breast acini probe the ECM with non-proteolytic actin microspikes, which, as functional precursors of invadopodia, widen pores in the collagen IV meshwork with force-transmitting focal adhesions and initiate BM penetration. In cells disseminating into the ECM, such non-proteolytic microspikes are then converted into proteolytically active invadopodia containing MMP-14. The formation of invadopodia is stimulated by ECM rigidity, degradation of ECM molecules, and growth factor signaling. As invadopodia mature, they elongate and expand through actin polymerization and cortactin-dependent actin branching, and lysosomal and late endosomal vesicles containing MMP-14 fuse with the invadopodial plasma membrane. By recycling from endosomal pools, MMP-14 is incorporated into invadopodia, where a high concentration of MMP-14 is maintained by anchoring MMP-14 to the invadopodial actin/cortactin core. Via the protrudin pathway, MMP-14 is brought to the base of invadopodia and, by means of the endosomal tubulation machinery, into the narrow invadopodia core and to the tip of invadopodia. MMP-14 remains restricted to the invadopodia, with dystroglycan and ECM adhesion proteins forming a barrier against lateral diffusion at the invadopodia base. During cancer cell invasion, cells switch back and forth between periods of integrin-mediated migration and invadosome-mediated matrix degradation and passage. Several non-receptor tyrosine kinases (NRTKs) jointly regulate invadopodia formation and function and, thus, control the balance between local tumor growth on the one hand and invasiveness and spread of tumor cells on the other hand. FAK counteracts the formation of invadopodia by withdrawing Src from invadopodia and recruiting it into focal adhesions. In contrast, PTK2B is responsible for recruitment and activation of Src and also for the phosphorylation of cortactin. While Src promotes the assembly of invadopodium precursor structures, which it stabilizes by phosphorylation of TKS5, PTK2B phosphorylates cortactin after activation by integrins or other signals, such as EGFR, both directly and indirectly via Src and the Abelson-related gene tyrosine kinase ABL2. This tyrosine-phosphorylated cortactin then activates several signaling pathways that result in actin polymerization, ECM degradation, and docking and secretion of exosomes, thus promoting invasion and dissemination of cancer cells.

72It is still open whether invadosomes and podosomes share a similar mechanosensory mechanism. In the three-dimensional ECM meshwork, mechanosensing and actin-based cell protrusions are controlled by p21-activated kinase 1 (PAK1). The mechanosensitive ion channel Piezo1, which activates in ECs the MMPs -2 and -14 and promotes translocation of MMP-14 to the plasma membrane, is highly expressed in breast cancer and gastric tumor cell lines where its inhibition and knockdown impede cell motility and migration.

73Prior to their extravasation, metastatic cancer cells and T-cells can project invadopodia-like protrusions (ILPs) at endothelial junctions into the extravascular stroma, likely to scout a potential site for diapedesis. This could explain why some cancers preferentially metastasize into different organs. Invadopodia-like structures, however, are not yet characterized for localized accumulation or secretion of proteases. Although proteases appear to be dispensable for transcellular pore formation, proteases on ILPs (1) could influence the local density of adhesion molecules and chemokines and, thus, the adhesion and signal dynamics at the endothelium, and (2) might be involved in BM penetration. ILPs also protrude forcefully from the bottom of T-cells, thereby indenting the endothelium and creating close contacts to ECs in so-called ILP footprints or podo-prints.

74To degrade larger areas of the ECM, larger, rosette-shaped aggregates of invadopodia can arise. HIC-5, a scaffold protein closely related to paxillin, is essential for the formation of such invadopodia rosettes.

75Another type of invadosomes is the so-called linear invadopodia. They differ significantly in their structure from invadopodia in the conventional sense, but also enable matrix remodeling by ECs and embryonic and cancer cells. Associated with collagen I fibrils, they have a linear organization of invadosome-typical scaffold proteins TKS5, Src, WASp, Arp2/3, and cortactin and have proteolytic activity thanks to MMPs -14 and -2. However, they lack integrins and other proteins such as vinculin and paxillin. Instead, they are regulated via DDR1 as a collagen receptor and CDC42 and its guanidine exchange factor Tuba.

4.6. A Sealing Zone Surrounds the Resorption Lacuna of Osteoclasts

76Podosomes are also instrumental in bone remodeling by osteoclasts, large multinucleated bone cells that resorb bone matrix. During the maturation of osteoclast precursors, groups of podosomes assemble into higher-order ring- and belt-like structures that eventually fuse to form a band-shaped sealing zone that delimits and, due to further tightening of its F-actin network, seals the resorption lacuna. Bone remodeling and homeostasis are controlled by several MMPs and cathepsin K. For example, bone catabolism depends on the cooperation of MMP-9 and MP-14 secreted by osteoclasts. The bioavailability and activity of TGF-β and BMPs is also regulated by MMPs.

77In contrast to the resorption zone, which is acidified by the vacuolar ATPase and the chloride-proton antiporter CLCN7, the sealing zone contains NHE-1 and, in this respect, is similar to invadopodia. Recruited by Src-dependent cortactin phosphorylation, NHE1 exchanges here locally extracellular Na+ for intracellular H+. The resulting increase in intracellular pH leads, via clustering of phosphatidyl-inositol-4,5-bisphosphate, to an activation of cofilin, thus regulating the actin-dependent pushing force of the cell protrusion. Src is required for the organization of the cytoskeleton in osteoclasts and is, therefore, indispensable for efficient bone resorption.

4.7. Invading Cancer Cells Can Cleave the ECM at Belt-Like Compressions That Impede Cell Migration

78After initial cleavage of the impeding ECM meshwork, cancer cells move forward. However, along their way through tight interstitial spaces, they are severely squeezed in this process, showing a belt-like compression. If the space between the collagen fibers in a dense ECM becomes increasingly narrow, the cell nucleus deforms to a certain extent, so that the cell can squeeze through narrow spaces down to 25 µm2 in cross section. However, when the ECM meshwork becomes too dense for migration, the cell locally degrades the ECM structures at the constriction site and generates small trail-like matrix defects.

5.1. MMPs Play an Essential Role in the Remodeling of Tumor Stroma ECM

79The ECM, which is much more than a mere structural framework and which regulates and fine-tunes practically all cellular processes from cell adhesion and migration to survival and proliferation, is usually modified biochemically, biomechanically, and topographically in cancer. It is subject to remodeling by cancer cells and other cells of the tumor stroma, such as CAFs. A frequent notion describing the TME is that a tumor resembles a wound that never heals. In fact, both show more similarities than differences. During normal wound healing, damaged blood vessels release coagulation factors. The resulting fibrin network not only stabilizes the thrombus and results in hemostasis but also serves as provisional ECM, into which fibroblasts and immune cells migrate to rebuild the damaged tissue. A solid tumor mass reaches blood vessels by growth or it attracts blood vessels. Either way, tumor cells infiltrate the EC layer, thereby causing blood components to leak into the surrounding tissue. Among them are coagulation factors that, similar to wound healing, generate a fibrin-rich ECM. Even before blood vessel leakage occurs, tumor cells induce the resident cells to change their behavior. Thus, fibroblasts differentiate into CAFs, which, with their myofibroblastic appearance and increased biosynthesis of ECM matrix components, raise the tension of the tumor matrix and modify the biophysical and biochemical composition of the TME. Stromal cells produce over 90% of a tumor’s ECM mass, mostly core matrisome proteins such as collagens, glycoproteins, and proteoglycans, while the far smaller yet more diverse proportion is from cancer cells. Remarkably, it is precisely these matrix proteins formed by cancer cells that correlate with a poor prognosis for the patient. CAFs are involved in all stages of cancer progression and in the host response to tissue damage by cancer cells. They also secrete a large number of cytokines, growth factors, proteoglycans, matricellular proteins, and matrix-degrading enzymes, which promote the growth and mobility of cancer cells. In addition, CAFs control the assembly of a rigid and anisotropic network of collagen I.

80Stimulated by cancer cells, resident and invading immune cells also develop into highly active cells that promote tumor progression. Both cancer and immune cells secrete soluble factors such as growth factors (GFs) and cytokines and, thus, induce the differentiation of fibroblasts into CAFs. MMPs affect various functions of the immune system in cancer progression. MMP-9 suppresses the proliferation of T-lymphocytes by shedding the interleukin-2 receptor-α from their surface and, like the MMPs -2 and -14, it impedes the reaction of T-lymphocytes against cancer cells by releasing TGF-β. The sensitivity of NK cells to cancer cells is decreased by the release of the α1 proteinase inhibitor by MMPs -1, -3, -7, -8, and -11. Moreover, MMPs -7 and -8 affect leucocyte infiltration by cleavage and mobilization of chemokines.

81The M2-like tumor-associated macrophages (TAMs) support the tumor by producing distinct MMPs, such as MMPs -2 and -9, in various tumor entities with poor prognosis. MMP-14 is upregulated in glioma cell lines by astrocyte-derived IL-6 and increases their migration and invasiveness. By activating MMP-2, MMP-14 can modulate the concentration of alarmin S100A9 and, thus, negatively regulate inflammatory reactions. In monocytes, the cytoplasmic tail of ICAM-1 interacts with MMP-14, and shedding of the ICAM-1 ectodomain by MMP-14 is essential for efficient endothelial transmigration.

82Altered ECM synthesis by CAFs and cancer cells results in a fibrotic process termed desmoplasia, in which overshooting collagen production by fibroblast results in a rigid meshwork of type I collagen-rich fibrils. By adhering to them, myofibroblastic CAFs set this meshwork under strong tension and cause an increased interstitial pressure typical of solid tumors. Conversely, ECM-cleaving MMPs, typically found during wound healing and in fibrotic processes, determine the turnover of the tumor stroma and reduce contact guidance by fibrillar matrix structures. They are needed by the motile tumor cells to penetrate the dense and tensed collagen network of the TME and tumor collagenous capsule. The triple-helical structure provides a slim stick-like appearance to the collagen molecule and bestows it with an exceptionally high resilience against proteolytic attack, in contrast to the non-triple-helical collagen chains forming the proteolytically highly accessible gelatin after the triple helix is melted. Only a selected set of proteinases, among them MMP-14, is able to cleave triple-helical collagens along a mechanism in which the triple helix is partially melted with the help of an auxiliary domain, such as the hemopexin domain. According to their distinct supramolecular arrangement, the different collagen types can be subdivided into, e.g., fibril-forming, network-forming, and fibril-associated collagens. While type I collagen, in association with type III and V collagens form fibrils typically scaffolding the interstitial stroma, type IV collagen shapes a chicken-wire network, which is a structural component of sheet-like BMs.

83Fibronectin is not only increased quantitatively in the tumor stroma, it is also qualitatively different. The supramolecular fibrin filaments consist of fibrin molecules, which are made of two disulfide-linked chains, which come in different splice variants. Conspicuously, the splice variants with the extradomains (ED) A and B, are predominantly expressed in the tumor stroma. They are otherwise found in fetal tissues during development and wound healing, but are also re-expressed in cancer cells. The fibronectin meshwork interlinks with the collagen network to form a scaffold, into which other ECM proteins are woven. Of special interest are proteins, which are abundant within the intermediate surroundings of cells. Such matricellular ECM proteins (reviewed in) are small leucine-rich proteins (SLRPs), such as decorin and versican and various other protein families, e.g., CCN proteins, tenascins, SIBLINGs, galectins, SPARC, thrombospondins, and periostin. They undergo characteristic changes during tumor progression. Tenascin W appears to be a characteristic marker of the TME.

84The ECM protein scaffold provides attachment points for cells, which adhere and sense it via cell adhesion molecules, among them integrins. Via integrins, they also exert mechanical forces onto the ECM meshwork, thereby setting it under tension. Stiffness and tension are two biophysical parameters that are sensed by cells and contribute to the characteristic TME. Moreover, mechanical tension releases TGF-β, which is tethered to the ECM in the non-tensed state. TGF-β strongly stimulates differentiation of CAFs, which in turn produce more ECM. Stiffness of the ECM scaffold can be increased by biochemical crosslinking of its molecules to form supramolecular complexes. Thus, in addition to increased deposition of collagen I, the TME and the metastatic niche are enriched in lysyl-oxidases (LOXs) and LOX-like proteins (LOXL), which crosslink collagen molecules via oxidatively derived lysyl side chains. Additionally, transglutaminase activity in the TME increases ECM rigidity.

85ECM rigidity is generally decreased by proteinases such as MMPs. Pericellular MMPs can selectively cleave ECM components in front of an invading cell to open its path through the ECM meshwork. Furthermore, by cleaving the γ-2 chain of laminin-5, MMP-14 and MMP-2 can release an EGF-like fragment that promotes EGFR-dependent cell motility and proliferation. Accordingly, various cleavage products of ECM proteins are able to serve as soluble cytokines. Hence, the name “matrikine” was coined for them. Growth factors and cytokines, as well as exosomes, are additional means of cell–cell communications within the TME.

86The acidification of the TME by lactic acid promotes the formation of invadopodia, the trafficking of lysosomes to these structures where they fuse with the plasma membrane, and the production of exosomes. This results in the release of lysosomal proteases and in incorporation of the vacuolar H+-ATPase of the lysosomal membrane into the invadopodial membrane, which, together with NHE-1, lowers the pH and favors EMC degradation. NHE1, recruited to invadopodia by phosphorylation of cortactin, acidifies the peri-invadopodial space and, thus, promotes the proteolysis of ECM components by MMPs -2 and -9. NHE1 also stimulates the expression of MMP-14 via ERK1/2 and p38-MAPK signaling in MDA-MB-231 breast cancer cells. By recruiting β1 integrin to the NHE1/NHERF1/p-ezrin signal complex, integrin-linked kinase (ILK) stimulates the proteolytic activity and invasion of invadopodia.

87The specific topography of collagen fibers at the tumor–stromal boundary is crucial in local invasion. Moreover, the stiffness of collagen, increased by LOX-mediated crosslinkages, triggers invasion-promoting signaling in premalignant epithelial cells. Mechanical forces that are exerted onto cancer cells by tissue tension or that the cancer cells exert on their surrounding TME are essentially involved in mechanotransduction-induced gene regulation and cancer cell migration and invasion.

5.2. MMPs Generate Bioactive Matrikines during Degradation and Remodeling of the ECM

88MMPs can cleave ECM components of the TME to release matrikines. These bioactive peptides regulate tumor progression and metastasis and can be used diagnostically. For example, degradation of perlecan by MMPs or cathepsins generates several fragments, in particular, the angiostatic endorepellin. Subsequent proteolytic cleavage of endorepellin by proteases and cathepsin L releases a laminin G-like domain, which binds α2β1 integrin.

89Additionally, plasma membrane-bound proteins such as the adhesion G protein-coupled receptor B1 (ADGRB1, BAI1), an orphan G protein-coupled receptor protein, can also be cleaved by MMP-14, thereby producing bioactive molecules with matrikine-like function, such as the angiogenesis-inhibiting vasculostatin-40.

90Conversely, the activity of MMPs is subject to regulation by matrikines. For example, lamstatin (NC1), the C-terminal domain of the α5 chain of type IV collagen, inhibits tumor cell migration by down-regulating both αvβ3 integrin and MMP-14. Similarly, hyaluronic acid (HA) oligosaccharide fragments released by glycosidases can modify the expression of MMPs.

6. Translational Perspectives: MMPs and Invadopodia Are Worthwhile Targets for Inhibiting Cancer Progression

91MMP levels increase with cancer stage and malignancy and are, hence, used as diagnostic and prognostic biomarkers. Moreover, the realization that MMPs significantly shape the TME has stimulated the development of tumor-targeting MMP-responsive nanomaterials and nanocarriers for cancer therapy. Such “smart” materials should enable the targeted delivery of drugs, imaging, and theranostic agents on the tissue, cell, and intracellular levels. While this strategy promises effective drug delivery and tumor targeting, its success, either alone or in combination with other therapies, remains to be seen.

92In addition to the use of MMP inhibitors, therapeutic approaches aimed at the structure and function of invadopodia or at the TME with its increased matrix rigidity are also conceivable in order to inhibit metastasis (Figure 8).

93Metastasis, the leading cause of death in cancer patients, occurs due to the ability of cancer cells to remodel and break down the surrounding ECM and invade other tissues. Invadopodia correlate with a poor prognosis in various cancers. Consequently, three conceivable routes to curb metastasis may be to target (1) select MMPs, (2) invadopodia, or (2) other components or the biomechanics of the TME. A deeper understanding of the underlying functional mechanisms is beneficial for the development of new markers and therapies.

94Although MMPs on the cell surface or in the extracellular compartment are, in principle, druggable, more than 50 different MMP inhibitors have so far proven to be unsuccessful in clinical studies. In a phase I/IIa clinical trial started in January 2018, the drug BT1718 is being studied in adult patients with advanced solid tumors. BT1718 is a ‘bicycle drug conjugate’ that targets and inhibits MMP-14. Upon binding to MMP-14, it is taken up by cancer cells and causes them to die. Other clinical trials on MMPs are described by. MMP inhibitors have recently been reviewed by.

95The biological activity of an MMP depends not only on its catalytic domain but also on so-called exosites on its other domains, e.g., the hemopexin domain that helps to unwind the collagen triple helix. Moreover, the large spectrum of MMP substrates may be another problem, as cleavage of one substrate protein, such as collagen, may help tumor progression, while release of a matrikine from another substrate by cleavage through the same MMP may have an opposite effect on tumor cells. The situation is further complicated by the observation that the same MMP may exert opposite effects on early vs. late stage of tumor progression. Therefore, ideally, inhibitors should be both MMP-specific and substrate-specific and, moreover, time-specific and specific for the subcellular location at which the respective MMP acts pathologically. There is a wide variety of MMP inhibitors of clinical relevance, ranging from hydroxamate-based inhibitors and new-generation hydroxamate-based inhibitors, over non-hydroxamate-based inhibitors to drugs that target alternative binding sites and antibody-based therapeutics, as well as endogenous inhibitors of MMP function. With respect to MMP-14, a monoclonal antibody that blocks MMP-14 abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.

96As compared to MMP inhibition, completely different therapeutic approaches are conceivable that target the structure and function of the invadopodia. After their first observation in Src-transformed fibroblasts, invadopodia have been detected in many invasive human cancer cells such as breast cancer, melanoma, and glioblastoma and correlate with poor prognosis. However, there is still no invadopodia-targeted cancer treatment. Research is underway on drug repurposing and the inhibition of proteins that are essential to invadopodia, such as signaling pathways, ion channels, or MMPs. Inhibition of NRTKs in the PTK2B-Src-ABL2-cortactin cascade, in particular of ABL2, effectively inhibits the invadopodia-mediated invasiveness and metastasis of human breast cancer cells in a mouse tumor model. The interaction between PTK2B and FAK in controlling the formation and function of invadopodia suggests the inhibition of both kinases in order to curb metastasis.

97The Src kinase inhibitor saracatinib prevents invadopodia formation in neck squamous cell carcinoma cells and in a chicken tumor model system. Direct inhibition of invadopodia formation by RNA interference against TKS4 or TKS5 also significantly reduces cancer extravasation in a mouse model. However, knockdown or inhibition of various components of invadopodia of already established secondary micro- or macrometastases does not reduce tumor growth. Even worse, paclitaxel increases both the incidence of invadopodia and the invasiveness of several human cancer cell lines, which raises concerns for its potential clinical use before neoadjuvant therapy or in patients with refractory tumors.

98The TME with its increased matrix rigidity could be another conceivable target for pharmacologically inhibiting cancer metastasis. Recent progress in targeting the TME in both drug development and clinical trials has been summarized by. The role of mechanical forces in cancer has now become clear and sparked the idea of using the physical properties of TME in a targeted manner. Several clinical studies with ECM-normalizing drugs and drugs that target mechanotransduction with a possible effect on MMP-14 function are currently underway. Targeting transglutaminase or lysyl oxidase with therapeutics could be options to fight cancer by reversing the biomechanical stiffening of the TME.

99ECM proteins derived from cancer cells or their regulators could be other potential therapeutic candidates. Lumican, a small, leucine-rich proteoglycan, can directly bind to and inhibit MMP-14 and, hence, may limit tumor progression by preventing collagen degradation and invasion. Lumican has an anti-tumor effect in breast cancer, pancreatic cancer, and malignant melanoma by counteracting MMP-14 signaling, among other things.

100Since the active form of MMP-14 appears to be a better biomarker than its gene expression, several fluorescence- and bioluminescence-based MMP activity reporter constructs have been developed to study the relationship between MMP-14 and the TME in vivo. The activities of other MMPs can also be investigated with nanoprobes. For example, there is a fluorescent nanoprobe for MMP-2 activity, which is not activated by membrane-tethered MMP-14.

101As knowledge of tumor cell dissemination and invasion increases, it becomes evident that a successful strategy to impede metastasis has to envision both adhesion and proteolysis.

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65.
McGuire J.K., Li Q., Parks W.C. Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am. J. Pathol. 2003;162:1831-1843.
Not in our library10.1016/s0002-9440(10)64318-0
66.
Lee Y.H., Park J.H., Cheon D.H., Kim T., Park Y.E., Oh E.S., Lee J.E., Lee S.T. Processing of syndecan-2 by matrix metalloproteinase-14 and effect of its cleavage on VEGF-induced tube formation of HUVECs. Bio Chem. J. 2017;474:3719-3732.
Not in our library10.1042/bcj20170340
67.
Holopainen J.M., Moilanen J.A., Sorsa T., Kivelä-Rajamäki M., Tervahartiala T., Vesaluoma M.H., Tervo T.M. Activation of matrix metalloproteinase-8 by membrane type 1-MMP and their expression in human tears after photorefractive keratectomy. Investig. Ophthalmol. Vis. Sci. 2003;44:2550-2556.
Not in our library10.1167/iovs.02-1190
68.
Miekus N., Luise C., Sippl W., Baczek T., Schmelzer C.E.H., Heinz A. MMP-14 degrades tropoelastin and elastin. Biochimie. 2019;165:32-39.
Not in our library10.1016/j.biochi.2019.07.001
69.
Murphy G., Nagase H. Progress in matrix metalloproteinase research. Mol. Asp. Med. 2008;29:290-308.
Not in our library10.1016/j.mam.2008.05.002
70.
Jackson B.C., Nebert D.W., Vasiliou V. Update of human and mouse matrix metalloproteinase families. Hum. Genomics. 2010;4:194-201.
Not in our library10.1186/1479-7364-4-3-194
71.
Cui N., Hu M., Khalil R.A. Biochemical and Biological Attributes of Matrix Metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017;147:1-73.
Not in our library10.1016/bs.pmbts.2017.02.005
72.
Mittal R., Patel A.P., Debs L.H., Nguyen D., Patel K., Grati M., Mittal J., Yan D., Chapagain P., Liu X.Z. Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions. J. Cell Physiol. 2016;231:2599-2621.
Not in our library10.1002/jcp.25430
73.
Gonzalez-Avila G., Sommer B., Mendoza-Posada D.A., Ramos C., Garcia-Hernandez A.A., Falfan-Valencia R. Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit. Rev. Oncol. Hematol. 2019;137:57-83.
Not in our library10.1016/j.critrevonc.2019.02.010
74.
Chang W.J., Du Y., Zhao X., Ma L.Y., Cao G.W. Inflammation-related factors predicting prognosis of gastric cancer. World J. Gastroenterol. 2014;20:4586-4596.
Not in our library10.3748/wjg.v20.i16.4586
75.
Liu C., Qu L., Zhao C., Shou C. Extracellular gamma-synuclein promotes tumor cell motility by activating β1 integrin-focal adhesion kinase signaling pathway and increasing matrix metalloproteinase-24,-2 protein secretion. J. Exp. Clin. Cancer Res. 2018;37:117.
Not in our library10.1186/s13046-018-0783-6
76.
Gutschalk C.M., Yanamandra A.K., Linde N., Meides A., Depner S., Mueller M.M. GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression. Cancer Med. 2013;2:117-129.
Not in our library10.1002/cam4.20
77.
Nagase H., Visse R., Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 2006;69:562-573.
Not in our library10.1016/j.cardiores.2005.12.002
78.
Van Wart H.E., Birkedal-Hansen H. The cysteine switch: A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl Acad Sci. USA. 1990;87:5578-5582.
Not in our library10.1073/pnas.87.14.5578
79.
Loffek S., Schilling O., Franzke C.W. Series “matrix metalloproteinases in lung health and disease”: Biological role of matrix metalloproteinases: A critical balance. Eur. Respir. J. 2011;38:191-208.
Not in our library10.1183/09031936.00146510
80.
Sato H., Kinoshita T., Takino T., Nakayama K., Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett. 1996;393:101-104.
Not in our library10.1016/0014-5793(96)00861-7
81.
Kang T., Nagase H., Pei D. Activation of membrane-type matrix metalloproteinase 3 zymogen by the proprotein convertase furin in the trans-Golgi network. Cancer Res. 2002;62:675-681.
Not in our library
82.
Regulation of Membrane Type-1 Matrix Metalloproteinase Activation by Proprotein Convertases · 2000
Not checked
83.
Bassi D.E., Lopez De Cicco R., Cenna J., Litwin S., Cukierman E., Klein-Szanto A.J. PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression. Cancer Res. 2005;65:7310-7319.
Not in our library10.1158/0008-5472.can-05-1213
84.
Starr A.E., Bellac C.L., Dufour A., Goebeler V., Overall C.M. Biochemical characterization and N-terminomics analysis of leukolysin, the membrane-type 6 matrix metalloprotease (MMP25): Chemokine and vimentin cleavages enhance cell migration and macrophage phagocytic activities. J. Biol. Chem. 2012;287:13382-13395.
Not in our library10.1074/jbc.m111.314179
85.
Falkowski K., Bielecka E., Thøgersen I.B., Bocheńska O., Płaza K., Kalińska M., Sąsiadek L., Magoch M., Pęcak A., Wiśniewska M., et al. Kallikrein-Related Peptidase 14 Activates Zymogens of Membrane Type Matrix Metalloproteinases (MT-MMPs)-A CleavEx Based Analysis. Int. J. Mol. Sci. 2020;21:4383.
Not in our library10.3390/ijms21124383
86.
Ohuchi E., Imai K., Fujii Y., Sato H., Seiki M., Okada Y. Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 1997;272:2446-2451.
Not in our library10.1074/jbc.272.4.2446
87.
Okada Y., Morodomi T., Enghild J.J., Suzuki K., Yasui A., Nakanishi I., Salvesen G., Nagase H. Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. Eur. J. Bio Chem. 1990;194:721-730.
Not in our library10.1111/j.1432-1033.1990.tb19462.x
88.
Butler G.S., Will H., Atkinson S.J., Murphy G. Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. Eur. J. Bio Chem. 1997;244:653-657.
Not in our library10.1111/j.1432-1033.1997.t01-1-00653.x
89.
Takino T., Sato H., Shinagawa A., Seiki M. Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family. J. Biol. Chem. 1995;270:23013-23020.
Not in our library10.1074/jbc.270.39.23013
90.
Pei D. Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. J. Biol. Chem. 1999;274:8925-8932.
Not in our library10.1074/jbc.274.13.8925
91.
Llano E., Pendás A.M., Freije J.P., Nakano A., Knäuper V., Murphy G., López-Otin C. Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. Cancer Res. 1999;59:2570-2576.
Not in our library
92.
Morrison C.J., Overall C.M. TIMP independence of matrix metalloproteinase (MMP)-2 activation by membrane type 2 (MT2)-MMP is determined by contributions of both the MT2-MMP catalytic and hemopexin C domains. J. Biol. Chem. 2006;281:26528-26539.
Not in our library10.1074/jbc.m603331200
93.
Shimada T., Nakamura H., Ohuchi E., Fujii Y., Murakami Y., Sato H., Seiki M., Okada Y. Characterization of a truncated recombinant form of human membrane type 3 matrix metalloproteinase. Eur. J. Bio Chem. 1999;262:907-914.
Not in our library10.1046/j.1432-1327.1999.00459.x
94.
Hiraoka N., Allen E., Apel I.J., Gyetko M.R., Weiss S.J. Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell. 1998;95:365-377.
Not in our library10.1016/s0092-8674(00)81768-7
95.
Hotary K.B., Yana I., Sabeh F., Li X.Y., Holmbeck K., Birkedal-Hansen H., Allen E.D., Hiraoka N., Weiss S.J. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and-independent processes. J. Exp. Med. 2002;195:295-308.
Not in our library10.1084/jem.20010815
96.
Ito E., Yana I., Fujita C., Irifune A., Takeda M., Madachi A., Mori S., Hamada Y., Kawaguchi N., Matsuura N. The role of MT2-MMP in cancer progression. Bio Chem. Biophys.. Res. Commun. 2010;393:222-227.
Not in our library10.1016/j.bbrc.2010.01.105
97.
Folgueras A.R., Valdés-Sánchez T., Llano E., Menéndez L., Baamonde A., Denlinger B.L., Belmonte C., Juárez L., Lastra A., García-Suárez O., et al. Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation. Proc. Natl. Acad. Sci. USA. 2009;106:16451-16456.
Not in our library10.1073/pnas.0908507106
98.
Cauwe B., Opdenakker G. Intracellular substrate cleavage: A novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases. Crit. Rev. Bio. Chem. Mol. Biol. 2010;45:351-423.
Not in our library10.3109/10409238.2010.501783
99.
Shofuda T., Shofuda K., Ferri N., Kenagy R.D., Raines E.W., Clowes A.W. Cleavage of focal adhesion kinase in vascular smooth muscle cells overexpressing membrane-type matrix metalloproteinases. Arterioscler. Thromb. Vasc. Biol. 2004;24:839-844.
Not in our library10.1161/01.atv.0000126680.78500.4c
100.
Sakamoto T., Seiki M. A membrane protease regulates energy production in macrophages by activating hypoxia-inducible factor-1 via a non-proteolytic mechanism. J. Biol. Chem. 2010;285:29951-29964.
Not in our library10.1074/jbc.m110.132704
101.
Gonzalo P., Guadamillas M.C., Hernández-Riquer M.V., Pollán A., Grande-García A., Bartolomé R.A., Vasanji A., Ambrogio C., Chiarle R., Teixidó J., et al. MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling. Dev. Cell. 2010;18:77-89.
Not in our library10.1016/j.devcel.2009.11.012
102.
Gingras D., Michaud M., Di Tomasso G., Béliveau E., Nyalendo C., Béliveau R. Sphingosine-1-phosphate induces the association of membrane-type 1 matrix metalloproteinase with p130Cas in endothelial cells. FEBS Lett. 2008;582:399-404.
Not in our library10.1016/j.febslet.2007.12.029
103.
Hoshino D., Tomari T., Nagano M., Koshikawa N., Seiki M. A novel protein associated with membrane-type 1 matrix metalloproteinase binds p27(kip1) and regulates RhoA activation, actin remodeling, and matrigel invasion. J. Biol. Chem. 2009;284:27315-27326.
Not in our library10.1074/jbc.m109.041400
104.
Kessenbrock K., Wang C.Y., Werb Z. Matrix metalloproteinases in stem cell regulation and cancer. Matrix Biol. 2015;44–46:184-190.
Not in our library10.1016/j.matbio.2015.01.022
105.
Egeblad M., Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer. 2002;2:161-174.
Not in our library10.1038/nrc745
106.
Yan C., Boyd D.D. Regulation of matrix metalloproteinase gene expression. J. Cell Physiol. 2007;211:19-26.
Not in our library10.1002/jcp.20948
107.
Vincenti M.P., Brinckerhoff C.E. Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: Can MMPs be good for you? J. Cell Physiol. 2007;213:355-364.
Not in our library10.1002/jcp.21208
108.
Chatterjee K., Jana S., Choudhary P., Swarnakar S. Triumph and tumult of matrix metalloproteinases and their crosstalk with eicosanoids in cancer. Cancer Metastasis Rev. 2018;37:279-288.
Not in our library10.1007/s10555-018-9756-7
109.
Kim Y.S., Joh T.H. Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders. Biomol. Ther. 2012;20:133-143.
Not in our library10.4062/biomolther.2012.20.2.133
110.
Johnson J.L., Pillai S., Pernazza D., Sebti S.M., Lawrence N.J., Chellappan S.P. Regulation of matrix metalloproteinase genes by E2F transcription factors: Rb-Raf-1 interaction as a novel target for metastatic disease. Cancer Res. 2012;72:516-526.
Not in our library10.1158/0008-5472.can-11-2647
111.
Li Y., Kuscu C., Banach A., Zhang Q., Pulkoski-Gross A., Kim D., Liu J., Roth E., Li E., Shroyer K.R., et al. miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14. Cancer Res. 2015;75:2674-2685.
Not in our library10.1158/0008-5472.can-14-2875
112.
Ma H., Wang L., Lv W., Lv Z. Effects of miR-7 on Hcy-induced rat cerebral arterial vascular smooth muscle cell proliferation, migration and inflammatory factor expression by targeting MMP-14 to regulate TLR4/NF-κB signaling pathway. Cell Mol. Biol. 2020;66:12-17.
Not in our library10.14715/cmb/2020.66.7.3
113.
Dai D., Feng X.D., Zhu W.Q., Bao Y.N. LncRNA BLACAT1 regulates the viability, migration and invasion of oral squamous cell carcinoma cells by targeting miR-142-5p. Eur. Rev. Med. Pharmacol. Sci. 2019;23:10313-10323.
Not in our library10.26355/eurrev_201912_19669
114.
Hsa_Circ_0007843 Acts as a mIR-518c-5p Sponge to Regulate the Migration and Invasion of Colon Cancer SW480 Cells · 2020
Not checked
115.
Djuric T., Zivkovic M., Travascio F. Overview of MMP Biology and Gene Associations in Human Diseases. The Role of Matrix Metalloproteinase in Human Body Pathologies. 2017;3-33.
Not in our library
116.
Buache E., Thai R., Wendling C., Alpy F., Page A., Chenard M.P., Dive V., Ruff M., Dejaegere A., Tomasetto C., et al. Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14. Cancer Med. 2014;3:1197-1210.
Not in our library10.1002/cam4.290
117.
Toth M., Hernandez-Barrantes S., Osenkowski P., Bernardo M.M., Gervasi D.C., Shimura Y., Meroueh O., Kotra L.P., Gálvez B.G., Arroyo A.G., et al. Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme. J. Biol. Chem. 2002;277:26340-26350.
Not in our library10.1074/jbc.m200655200
118.
Jackson H.W., Defamie V., Waterhouse P., Khokha R. TIMPs: Versatile extracellular regulators in cancer. Nat. Rev. Cancer. 2017;17:38-53.
Not in our library10.1038/nrc.2016.115
119.
Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol. 2011;12:233.
Not in our library10.1186/gb-2011-12-11-233
120.
Strongin A.Y., Collier I., Bannikov G., Marmer B.L., Grant G.A., Goldberg G.I. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J. Biol. Chem. 1995;270:5331-5338.
Not in our library10.1074/jbc.270.10.5331
121.
Ogata Y., Itoh Y., Nagase H. Steps involved in activation of the pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of metalloproteinases-1 complex by 4-aminophenylmercuric acetate and proteinases. J. Biol. Chem. 1995;270:18506-18511.
Not in our library10.1074/jbc.270.31.18506
122.
Itoh Y., Seiki M. MT1-MMP: A potent modifier of pericellular microenvironment. J. Cell Physiol. 2006;206:1-8.
Not in our library10.1002/jcp.20431
123.
Zucker S., Drews M., Conner C., Foda H.D., DeClerck Y.A., Langley K.E., Bahou W.F., Docherty A.J., Cao J. Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J. Biol. Chem. 1998;273:1216-1222.
Not in our library10.1074/jbc.273.2.1216
124.
Itoh Y., Ito N., Nagase H., Seiki M. The second dimer interface of MT1-MMP, the transmembrane domain, is essential for ProMMP-2 activation on the cell surface. J. Biol. Chem. 2008;283:13053-13062.
Not in our library10.1074/jbc.m709327200
125.
Knäuper V., Bailey L., Worley J.R., Soloway P., Patterson M.L., Murphy G. Cellular activation of proMMP-13 by MT1-MMP depends on the C-terminal domain of MMP-13. FEBS Lett. 2002;532:127-130.
Not in our library10.1016/s0014-5793(02)03654-2
126.
Gifford V., Itoh Y. MT1-MMP-dependent cell migration: Proteolytic and non-proteolytic mechanisms. Bio. Chem. Soc. Trans. 2019;47:811-826.
Not in our library10.1042/bst20180363
127.
Chernov A.V., Sounni N.E., Remacle A.G., Strongin A.Y. Epigenetic control of the invasion-promoting MT1-MMP/MMP-2/TIMP-2 axis in cancer cells. J. Biol. Chem. 2009;284:12727-12734.
Not in our library10.1074/jbc.m900273200
128.
Jiang D., He Z., Wang C., Zhou Y., Li F., Pu W., Zhang X., Feng X., Zhang M., Yecheng X., et al. Epigenetic silencing of ZNF132 mediated by methylation-sensitive Sp1 binding promotes cancer progression in esophageal squamous cell carcinoma. Cell Death Dis. 2018;10:1.
Not in our library10.1038/s41419-018-1236-z
129.
Lohi J., Lehti K., Valtanen H., Parks W.C., Keski-Oja J. Structural analysis and promoter characterization of the human membrane-type matrix metalloproteinase-1 (MT1-MMP) gene. Gene. 2000;242:75-86.
Not in our library10.1016/s0378-1119(99)00549-1
130.
Rowe R.G., Li X.Y., Hu Y., Saunders T.L., Virtanen I., Garcia de Herreros A., Becker K.F., Ingvarsen S., Engelholm L.H., Bommer G.T., et al. Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J. Cell Biol. 2009;184:399-408.
Not in our library10.1083/jcb.200810113
131.
Carver E.A., Jiang R., Lan Y., Oram K.F., Gridley T. The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol. Cell Biol. 2001;21:8184-8188.
Not in our library10.1128/mcb.21.23.8184-8188.2001
132.
Cha H.J., Okada A., Kim K.W., Sato H., Seiki M. Identification of cis-acting promoter elements that support expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) in v-src transformed Madin-Darby canine kidney cells. Clin. Exp. Metastasis. 2000;18:675-681.
Not in our library10.1023/a:1013190118556
133.
PROX1 is a transcriptional regulator of MMP14 · 2018
Not checked
134.
Lohi J., Lehti K., Westermarck J., Kähäri V.M., Keski-Oja J. Regulation of membrane-type matrix metalloproteinase-1 expression by growth factors and phorbol 12-myristate 13-acetate. Eur. J. Bio Chem. 1996;239:239-247.
Not in our library10.1111/j.1432-1033.1996.0239u.x
135.
Elsir T., Smits A., Lindström M.S., Nistér M. Transcription factor PROX1: Its role in development and cancer. Cancer Metastasis Rev. 2012;31:793-805.
Not in our library10.1007/s10555-012-9390-8
136.
Paszek M.J., Zahir N., Johnson K.R., Lakins J.N., Rozenberg G.I., Gefen A., Reinhart-King C.A., Margulies S.S., Dembo M., Boettiger D., et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8:241-254.
Not in our library10.1016/j.ccr.2005.08.010
137.
Borrirukwanit K., Pavasant P., Blick T., Lafleur M.A., Thompson E.W. High threshold of β1 integrin inhibition required to block collagen I-induced membrane type-1 matrix metalloproteinase (MT1-MMP) activation of matrix metalloproteinase 2 (MMP-2). Cancer Cell Int. 2014;14:99.
Not in our library10.1186/s12935-014-0099-3
138.
Zigrino P., Drescher C., Mauch C. Collagen-induced proMMP-2 activation by MT1-MMP in human dermal fibroblasts and the possible role of alpha2beta1 integrins. Eur. J. Cell Biol. 2001;80:68-77.
Not in our library10.1078/0171-9335-00134
139.
Sakai K., Nakamura T., Suzuki Y., Imizu T., Matsumoto K. 3-D collagen-dependent cell surface expression of MT1-MMP and MMP-2 activation regardless of integrin β1 function and matrix stiffness. Bio. Chem. Biophys. Res. Commun. 2011;412:98-103.
Not in our library10.1016/j.bbrc.2011.07.050
140.
Haas T.L., Stitelman D., Davis S.J., Apte S.S., Madri J.A. Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium. J. Biol. Chem. 1999;274:22679-22685.
Not in our library10.1074/jbc.274.32.22679
141.
Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., Seiki M. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 1994;370:61-65.
Not in our library10.1038/370061a0
142.
Roghi C., Jones L., Gratian M., English W.R., Murphy G. Golgi reassembly stacking protein 55 interacts with membrane-type (MT) 1-matrix metalloprotease (MMP) and furin and plays a role in the activation of the MT1-MMP zymogen. FEBS J. 2010;277:3158-3175.
Not in our library10.1111/j.1742-4658.2010.07723.x
143.
Hypoxia-regulated target genes implicated in tumor metastasis · 2012
No notice
144.
Liu W., Shen S.M., Zhao X.Y., Chen G.Q. Targeted genes and interacting proteins of hypoxia inducible factor-1. Int. J. Bio Chem. Mol. Biol. 2012;3:165-178.
Not in our library
145.
Kuscu C., Evensen N., Cao J. MMP14 (matrix metallopeptidase 14 (membrane-inserted)). Atlas Genet. Cytogenet. Oncol. Haematol. 2011.
Not in our library10.4267/2042/45036
146.
Yan S.F., Lu J., Zou Y.S., Soh-Won J., Cohen D.M., Buttrick P.M., Cooper D.R., Steinberg S.F., Mackman N., Pinsky D.J., et al. Hypoxia-associated induction of early growth response-1 gene expression. J. Biol. Chem. 1999;274:15030-15040.
Not in our library10.1074/jbc.274.21.15030
147.
Miyoshi A., Kitajima Y., Ide T., Ohtaka K., Nagasawa H., Uto Y., Hori H., Miyazaki K. Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-1alpha-independent manner. Int. J. Oncol. 2006;29:1533-1539.
Not in our library10.3892/ijo.29.6.1533
148.
Petrella B.L., Lohi J., Brinckerhoff C.E. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel-Lindau renal cell carcinoma. Oncogene. 2005;24:1043-1052.
Not in our library10.1038/sj.onc.1208305
149.
Muñoz-Nájar U.M., Neurath K.M., Vumbaca F., Claffey K.P. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene. 2006;25:2379-2392.
Not in our library10.1038/sj.onc.1209273
150.
Sakamoto T., Seiki M. Integrated functions of membrane-type 1 matrix metalloproteinase in regulating cancer malignancy: Beyond a proteinase. Cancer Sci. 2017;108:1095-1100.
Not in our library10.1111/cas.13231
151.
Zhu S., Zhou Y., Wang L., Zhang J., Wu H., Xiong J., Zhang J., Tian Y., Wang C., Wu H. Transcriptional upregulation of MT2-MMP in response to hypoxia is promoted by HIF-1α in cancer cells. Mol. Carcinog. 2011;50:770-780.
Not in our library10.1002/mc.20678
152.
Choi J.Y., Jang Y.S., Min S.Y., Song J.Y. Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions. J. Breast Cancer. 2011;14:88-95.
Not in our library10.4048/jbc.2011.14.2.88
153.
Infante E., Castagnino A., Ferrari R., Monteiro P., Agüera-González S., Paul-Gilloteaux P., Domingues M.J., Maiuri P., Raab M., Shanahan C.M., et al. LINC complex-Lis1 interplay controls MT1-MMP matrix digest-on-demand response for confined tumor cell migration. Nat. Commun. 2018;9:2443.
Not in our library10.1038/s41467-018-04865-7
154.
Chen S., Han M., Chen W., He Y., Huang B., Zhao P., Huang Q., Gao L., Qu X., Li X. KIF1B promotes glioma migration and invasion via cell surface localization of MT1-MMP. Oncol. Rep. 2016;35:971-977.
Not in our library10.3892/or.2015.4426
155.
Bravo-Cordero J.J., Marrero-Diaz R., Megías D., Genís L., García-Grande A., García M.A., Arroyo A.G., Montoya M.C. MT1-MMP proinvasive activity is regulated by a novel Rab8-dependent exocytic pathway. EMBO J. 2007;26:1499-1510.
Not in our library10.1038/sj.emboj.7601606
156.
Wolf K., Te Lindert M., Krause M., Alexander S., Te Riet J., Willis A.L., Hoffman R.M., Figdor C.G., Weiss S.J., Friedl P. Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 2013;201:1069-1084.
Not in our library10.1083/jcb.201210152
157.
Poincloux R., Lizarraga F., Chavrier P. Matrix invasion by tumour cells: A focus on MT1-MMP trafficking to invadopodia. J. Cell Sci. 2009;122:3015-3024.
Not in our library10.1242/jcs.034561
158.
Mori H., Lo A.T., Inman J.L., Alcaraz J., Ghajar C.M., Mott J.D., Nelson C.M., Chen C.S., Zhang H., Bascom J.L., et al. Transmembrane/cytoplasmic, rather than catalytic, domains of Mmp14 signal to MAPK activation and mammary branching morphogenesis via binding to integrin β1. Development. 2013;140:343-352.
Not in our library10.1242/dev.084236
159.
Pedersen N.M., Wenzel E.M., Wang L., Antoine S., Chavrier P., Stenmark H., Raiborg C. Protrudin-mediated ER-endosome contact sites promote MT1-MMP exocytosis and cell invasion. J. Cell Biol. 2020;219:e202003063.
Not in our library10.1083/jcb.202003063
160.
Hsu K.S., Otsu W., Li Y., Wang H.C., Chen S., Tsang S.H., Chuang J.Z., Sung C.H. CLIC4 regulates late endosomal trafficking and matrix degradation activity of MMP14 at focal adhesions in RPE cells. Sci. Rep. 2019;9:12247.
Not in our library10.1038/s41598-019-48438-0
161.
Grafinger O.R., Gorshtein G., Stirling T., Brasher M.I., Coppolino M.G. beta1 integrin-mediated signaling regulates MT1-MMP phosphorylation to promote tumor cell invasion. J. Cell Sci. 2020;133:jcs239152.
Not in our library10.1242/jcs.239152
162.
Ellerbroek S.M., Wu Y.I., Overall C.M., Stack M.S. Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J. Biol. Chem. 2001;276:24833-24842.
Not in our library10.1074/jbc.m005631200
163.
Weaver S.A., Wolters B., Ito N., Woskowicz A.M., Kaneko K., Shitomi Y., Seiki M., Itoh Y. Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix. J. Cell Sci. 2014;127:1203-1213.
Not in our library10.1242/jcs.135236
164.
Itoh Y. MT1-MMP: A key regulator of cell migration in tissue. IUBMB Life. 2006;58:589-596.
Not in our library10.1080/15216540600962818
165.
Oh J., Takahashi R., Kondo S., Mizoguchi A., Adachi E., Sasahara R.M., Nishimura S., Imamura Y., Kitayama H., Alexander D.B., et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell. 2001;107:789-800.
Not in our library10.1016/s0092-8674(01)00597-9
166.
Nakada M., Yamada A., Takino T., Miyamori H., Takahashi T., Yamashita J., Sato H. Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes. Cancer Res. 2001;61:8896-8902.
Not in our library
167.
Leco K.J., Waterhouse P., Sanchez O.H., Gowing K.L., Poole A.R., Wakeham A., Mak T.W., Khokha R. Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J. Clin. Investig. 2001;108:817-829.
Not in our library10.1172/jci200112067
168.
English J.L., Kassiri Z., Koskivirta I., Atkinson S.J., Di Grappa M., Soloway P.D., Nagase H., Vuorio E., Murphy G., Khokha R. Individual Timp deficiencies differentially impact pro-MMP-2 activation. J. Biol. Chem. 2006;281:10337-10346.
Not in our library10.1074/jbc.m512009200
169.
Albrechtsen R., Kveiborg M., Stautz D., Vikeså J., Noer J.B., Kotzsh A., Nielsen F.C., Wewer U.M., Fröhlich C. ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis and increased tumor growth. J. Cell Sci. 2013;126:4707-4720.
Not in our library10.1242/jcs.129510
170.
Itoh Y., Ito N., Nagase H., Evans R.D., Bird S.A., Seiki M. Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP. Mol. Biol. Cell. 2006;17:5390-5399.
Not in our library10.1091/mbc.e06-08-0740
171.
Pahwa S., Stawikowski M.J., Fields G.B. Monitoring and inhibiting MT1-MMP during cancer initiation and progression. Cancers. 2014;6:416-435.
Not in our library10.3390/cancers6010416
172.
Pahwa S., Bhowmick M., Amar S., Cao J., Strongin A.Y., Fridman R., Weiss S.J., Fields G.B. Characterization and regulation of MT1-MMP cell surface-associated activity. Chem. Biol. Drug Des. 2019;93:1251-1264.
Not in our library10.1111/cbdd.13450
173.
Nguyen A.T., Chia J., Ros M., Hui K.M., Saltel F., Bard F. Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis. Cancer Cell. 2017;32:639-653.e6.
Not in our library10.1016/j.ccell.2017.10.001
174.
Itoh Y., Seiki M. MT1-MMP: An enzyme with multidimensional regulation. Trends Bio Chem. Sci. 2004;29:285-289.
Not in our library10.1016/j.tibs.2004.04.001
175.
Remacle A., Murphy G., Roghi C. Membrane type I-matrix metalloproteinase (MT1-MMP) is internalised by two different pathways and is recycled to the cell surface. J. Cell Sci. 2003;116:3905-3916.
Not in our library10.1242/jcs.00710
176.
Uekita T., Itoh Y., Yana I., Ohno H., Seiki M. Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J. Cell Biol. 2001;155:1345-1356.
Not in our library10.1083/jcb.200108112
177.
Anilkumar N., Uekita T., Couchman J.R., Nagase H., Seiki M., Itoh Y. Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migration. FASEB J. 2005;19:1326-1328.
Not in our library10.1096/fj.04-3651fje
178.
Kruglikov I.L., Joffin N., Scherer P.E. The MMP14-caveolin axis and its potential relevance for lipoedema. Nat. Rev. Endocrinol. 2020;16:669-674.
Not in our library10.1038/s41574-020-0395-z
179.
Planchon D., Rios Morris E., Genest M., Comunale F., Vacher S., Bièche I., Denisov E.V., Tashireva L.A., Perelmuter V.M., Linder S., et al. MT1-MMP targeting to endolysosomes is mediated by upregulation of flotillins. J. Cell Sci. 2018;131:jcs218925.
Not in our library10.1242/jcs.218925
180.
Labrecque L., Nyalendo C., Langlois S., Durocher Y., Roghi C., Murphy G., Gingras D., Béliveau R. Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. J. Biol. Chem. 2004;279:52132-52140.
Not in our library10.1074/jbc.m409617200
181.
Williams K.C., Coppolino M.G. Phosphorylation of membrane type 1-matrix metalloproteinase (MT1-MMP) and its vesicle-associated membrane protein 7 (VAMP7)-dependent trafficking facilitate cell invasion and migration. J. Biol. Chem. 2011;286:43405-43416.
Not in our library10.1074/jbc.m111.297069
182.
Baldassarre T., Watt K., Truesdell P., Meens J., Schneider M.M., Sengupta S.K., Craig A.W. Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis. Mol. Cancer Res. 2015;13:1044-1055.
Not in our library10.1158/1541-7786.mcr-14-0573
183.
Wang X., Ma D., Keski-Oja J., Pei D. Co-recycling of MT1-MMP and MT3-MMP through the trans-Golgi network. Identification of DKV582 as a recycling signal. J. Biol. Chem. 2004;279:9331-9336.
Not in our library10.1074/jbc.m312369200
184.
El Azzouzi K., Wiesner C., Linder S. Metalloproteinase MT1-MMP islets act as memory devices for podosome reemergence. J. Cell Biol. 2016;213:109-125.
Not in our library10.1083/jcb.201510043
185.
Lehti K., Lohi J., Valtanen H., Keski-Oja J. Proteolytic processing of membrane-type-1 matrix metalloproteinase is associated with gelatinase A activation at the cell surface. Bio Chem. J. 1998;334:345-353.
Not in our library10.1042/bj3340345
186.
Stanton H., Gavrilovic J., Atkinson S.J., d’Ortho M.P., Yamada K.M., Zardi L., Murphy G. The activation of ProMMP-2 (gelatinase A) by HT1080 fibrosarcoma cells is promoted by culture on a fibronectin substrate and is concomitant with an increase in processing of MT1-MMP (MMP-14) to a 45 kDa form. J. Cell Sci. 1998;111:2789-2798.
Not in our library10.1242/jcs.111.18.2789
187.
Osenkowski P., Toth M., Fridman R. Processing, shedding, and endocytosis of membrane type 1-matrix metalloproteinase (MT1-MMP). J. Cell Physiol. 2004;200:2-10.
Not in our library10.1002/jcp.20064
188.
Tobar N., Avalos M.C., Méndez N., Smith P.C., Bernabeu C., Quintanilla M., Martínez J. Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells. Carcinogenesis. 2014;35:1770-1779.
Not in our library10.1093/carcin/bgu061
189.
Laudanski P., Swiatecka J., Kozlowski L., Lesniewska M., Wojtukiewicz M., Wolczynski S. Increased serum level of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) in patients with breast cancer. Folia Histo Chem. Cyto Biol. 2010;48:101-103.
Not in our library10.2478/v10042-009-0085-0
190.
Hotary K., Allen E., Punturieri A., Yana I., Weiss S.J. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. Cell Biol. 2000;149:1309-1323.
Not in our library10.1083/jcb.149.6.1309
191.
Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I · 2000
Not checked
192.
Gutiérrez-Fernández A., Soria-Valles C., Osorio F.G., Gutiérrez-Abril J., Garabaya C., Aguirre A., Fueyo A., Fernández-García M.S., Puente X.S., López-Otín C. Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid. EMBO J. 2015;34:1875-1888.
Not in our library10.15252/embj.201490594
193.
Knapinska A.M., Fields G.B. The Expanding Role of MT1-MMP in Cancer Progression. Pharmaceuticals. 2019;12:77.
Not in our library10.3390/ph12020077
194.
Karsdal M.A., Larsen L., Engsig M.T., Lou H., Ferreras M., Lochter A., Delaisse J.M., Foged N.T. Matrix metalloproteinase-dependent activation of latent transforming growth factor-beta controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J. Biol. Chem. 2002;277:44061-44067.
Not in our library10.1074/jbc.m207205200
195.
Tatti O., Vehviläinen P., Lehti K., Keski-Oja J. MT1-MMP releases latent TGF-beta1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1. Exp. Cell Res. 2008;314:2501-2514.
Not in our library10.1016/j.yexcr.2008.05.018
196.
McQuibban G.A., Butler G.S., Gong J.H., Bendall L., Power C., Clark-Lewis I., Overall C.M. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J. Biol. Chem. 2001;276:43503-43508.
Not in our library10.1074/jbc.m107736200
197.
Barbolina M.V., Stack M.S. Membrane type 1-matrix metalloproteinase: Substrate diversity in pericellular proteolysis. Semin. Cell Dev. Biol. 2008;19:24-33.
Not in our library10.1016/j.semcdb.2007.06.008
198.
Hotary K., Li X.Y., Allen E., Stevens S.L., Weiss S.J. A cancer cell metalloprotease triad regulates the basement membrane transmigration program. Genes Dev. 2006;20:2673-2686.
Not in our library10.1101/gad.1451806
199.
Friedl P., Wolf K. Tube travel: The role of proteases in individual and collective cancer cell invasion. Cancer Res. 2008;68:7247-7249.
Not in our library10.1158/0008-5472.can-08-0784
200.
Sabeh F., Ota I., Holmbeck K., Birkedal-Hansen H., Soloway P., Balbin M., Lopez-Otin C., Shapiro S., Inada M., Krane S., et al. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J. Cell Biol. 2004;167:769-781.
Not in our library10.1083/jcb.200408028
201.
Wolf K., Wu Y.I., Liu Y., Geiger J., Tam E., Overall C., Stack M.S., Friedl P. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat. Cell Biol. 2007;9:893-904.
Not in our library10.1038/ncb1616
202.
Marcink T.C., Simoncic J.A., An B., Knapinska A.M., Fulcher Y.G., Akkaladevi N., Fields G.B., Van Doren S.R. MT1-MMP Binds Membranes by Opposite Tips of Its beta Propeller to Position It for Pericellular Proteolysis. Structure. 2019;27:281-292.e6.
Not in our library10.1016/j.str.2018.10.008
203.
Ito K., Okamoto I., Araki N., Kawano Y., Nakao M., Fujiyama S., Tomita K., Mimori T., Saya H. Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of beta-catenin from cell-cell contacts. Oncogene. 1999;18:7080-7090.
Not in our library10.1038/sj.onc.1203191
204.
Steinhusen U., Weiske J., Badock V., Tauber R., Bommert K., Huber O. Cleavage and shedding of E-cadherin after induction of apoptosis. J. Biol. Chem. 2001;276:4972-4980.
Not in our library10.1074/jbc.m006102200
205.
Miyazawa Y., Uekita T., Ito Y., Seiki M., Yamaguchi H., Sakai R. CDCP1 regulates the function of MT1-MMP and invadopodia-mediated invasion of cancer cells. Mol. Cancer Res. 2013;11:628-637.
Not in our library10.1158/1541-7786.mcr-12-0544
206.
David J.M., Rajasekaran A.K. Dishonorable discharge: The oncogenic roles of cleaved E-cadherin fragments. Cancer Res. 2012;72:2917-2923.
Not in our library10.1158/0008-5472.can-11-3498
207.
Kajita M., Itoh Y., Chiba T., Mori H., Okada A., Kinoh H., Seiki M. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J. Cell Biol. 2001;153:893-904.
Not in our library10.1083/jcb.153.5.893
208.
Koshikawa N., Mizushima H., Minegishi T., Iwamoto R., Mekada E., Seiki M. Membrane type 1-matrix metalloproteinase cleaves off the NH2-terminal portion of heparin-binding epidermal growth factor and converts it into a heparin-independent growth factor. Cancer Res. 2010;70:6093-6103.
Not in our library10.1158/0008-5472.can-10-0346
209.
Miyazono K. Ectodomain shedding of HB-EGF: A potential target for cancer therapy. J. Bio Chem. 2012;151:1-3.
Not in our library10.1093/jb/mvr120
210.
Chan K.M., Wong H.L., Jin G., Liu B., Cao R., Cao Y., Lehti K., Tryggvason K., Zhou Z. MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis. Dev. Cell. 2012;22:1176-1190.
Not in our library10.1016/j.devcel.2012.04.014
211.
Nagano O., Murakami D., Hartmann D., De Strooper B., Saftig P., Iwatsubo T., Nakajima M., Shinohara M., Saya H. Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2+) influx and PKC activation. J. Cell Biol. 2004;165:893-902.
Not in our library10.1083/jcb.200310024
212.
Endo K., Takino T., Miyamori H., Kinsen H., Yoshizaki T., Furukawa M., Sato H. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J. Biol. Chem. 2003;278:40764-40770.
Not in our library10.1074/jbc.m306736200
213.
Deryugina E.I., Ratnikov B.I., Postnova T.I., Rozanov D.V., Strongin A.Y. Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase. J. Biol. Chem. 2002;277:9749-9756.
Not in our library10.1074/jbc.m110269200
214.
Golubkov V.S., Chekanov A.V., Cieplak P., Aleshin A.E., Chernov A.V., Zhu W., Radichev I.A., Zhang D., Dong P.D., Strongin A.Y. The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: Implications in cancer and embryogenesis. J. Biol. Chem. 2010;285:35740-35749.
Not in our library10.1074/jbc.m110.165159
215.
Golubkov V.S., Boyd S., Savinov A.Y., Chekanov A.V., Osterman A.L., Remacle A., Rozanov D.V., Doxsey S.J., Strongin A.Y. Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability. J. Biol. Chem. 2005;280:25079-25086.
Not in our library10.1074/jbc.m502779200
216.
Wali N., Hosokawa K., Malik S., Saito H., Miyaguchi K., Imajoh-Ohmi S., Miki Y., Nakanishi A. Centrosomal BRCA2 is a target protein of membrane type-1 matrix metalloproteinase (MT1-MMP). Bio. Chem. Biophys. Res. Commun. 2014;443:1148-1154.
Not in our library10.1016/j.bbrc.2013.12.103
217.
Mori H., Bhat R., Bruni-Cardoso A., Chen E.I., Jorgens D.M., Coutinho K., Louie K., Bowen B.B., Inman J.L., Tecca V., et al. New insight into the role of MMP14 in metabolic balance. Peer J. 2016;4:e2142.
Not in our library10.7717/peerj.2142
218.
Hoang B.H., Kubo T., Healey J.H., Yang R., Nathan S.S., Kolb E.A., Mazza B., Meyers P.A., Gorlick R. Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Cancer Res. 2004;64:2734-2739.
Not in our library10.1158/0008-5472.can-03-1952
219.
Saeb-Parsy K., Veerakumarasivam A., Wallard M.J., Thorne N., Kawano Y., Murphy G., Neal D.E., Mills I.G., Kelly J.D. MT1-MMP regulates urothelial cell invasion via transcriptional regulation of Dickkopf-3. Br. J. Cancer. 2008;99:663-669.
Not in our library10.1038/sj.bjc.6604513
220.
Shimizu-Hirota R., Xiong W., Baxter B.T., Kunkel S.L., Maillard I., Chen X.W., Sabeh F., Liu R., Li X.Y., Weiss S.J. MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev. 2012;26:395-413.
Not in our library10.1101/gad.178749.111
221.
Turunen S.P., Tatti-Bugaeva O., Lehti K. Membrane-type matrix metalloproteases as diverse effectors of cancer progression. Biochim. Biophys. Acta Mol. Cell Res. 2017;1864 Pt A:1974-1988.
Not in our library10.1016/j.bbamcr.2017.04.002
222.
Ota I., Li X.Y., Hu Y., Weiss S.J. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc. Natl. Acad. Sci. USA. 2009;106:20318-20323.
Not in our library10.1073/pnas.0910962106
223.
Hamidi H., Ivaska J. Every step of the way: Integrins in cancer progression and metastasis. Nat. Rev. Cancer. 2018;18:533-548.
Not in our library10.1038/s41568-018-0038-z
224.
Nikolopoulou P.A., Koufaki M.A., Kostourou V. The Adhesome Network: Key Components Shaping the Tumour Stroma. Cancers. 2021;13:525.
Not in our library10.3390/cancers13030525
225.
Winograd-Katz S.E., Fassler R., Geiger B., Legate K.R. The integrin adhesome: From genes and proteins to human disease. Nat. Rev. Mol. Cell Biol. 2014;15:273-288.
Not in our library10.1038/nrm3769
226.
Adhesion rings surround invadopodia and promote maturation · 2012
Not checked
227.
Zaidel-Bar R., Itzkovitz S., Ma’ayan A., Iyengar R., Geiger B. Functional atlas of the integrin adhesome. Nat. Cell Biol. 2007;9:858-867.
Not in our library10.1038/ncb0807-858
228.
Pelaez R., Pariente A., Perez-Sala A., Larrayoz I.M. Integrins: Moonlighting Proteins in Invadosome Formation. Cancers (Basel). 2019;11:615.
Not in our library10.3390/cancers11050615
229.
Mishra Y.G., Manavathi B. Focal adhesion dynamics in cellular function and disease. Cell Signal. 2021;85:110046.
Not in our library10.1016/j.cellsig.2021.110046
230.
Revach O.Y., Grosheva I., Geiger B. Biomechanical regulation of focal adhesion and invadopodia formation. J. Cell Sci. 2020;133:jcs244848.
Not in our library10.1242/jcs.244848
231.
Barber-Perez N., Georgiadou M., Guzman C., Isomursu A., Hamidi H., Ivaska J. Mechano-responsiveness of fibrillar adhesions on stiffness-gradient gels. J. Cell Sci. 2020;133:jcs242909.
Not in our library10.1242/jcs.242909
232.
Linder S. Invadosomes at a glance. J. Cell Sci. 2009;122:3009-3013.
Not in our library10.1242/jcs.032631
233.
Linder S., Cervero P. The podosome cap: Past, present, perspective. Eur. J. Cell Biol. 2020;99:151087.
Not in our library10.1016/j.ejcb.2020.151087
234.
Alonso F., Spuul P., Genot E. Podosomes in endothelial cell-microenvironment interactions. Curr. Opin. Hematol. 2020;27:197-205.
Not in our library10.1097/moh.0000000000000575
235.
T Lymphocyte–Endothelial Interactions: Emerging Understanding of Trafficking and Antigen-Specific Immunity · 2015
No notice
236.
Takito J., Inoue S., Nakamura M. The Sealing Zone in Osteoclasts: A Self-Organized Structure on the Bone. Int. J. Mol. Sci. 2018;19:984.
Not in our library10.3390/ijms19040984
237.
Augoff K., Hryniewicz-Jankowska A., Tabola R. Invadopodia: Clearing the way for cancer cell invasion. Ann. Transl. Med. 2020;8:902.
Not in our library10.21037/atm.2020.02.157
238.
Carman C.V., Sage P.T., Sciuto T.E., de la Fuente M.A., Geha R.S., Ochs H.D., Dvorak H.F., Dvorak A.M., Springer T.A. Transcellular diapedesis is initiated by invasive podosomes. Immunity. 2007;26:784-797.
Not in our library10.1016/j.immuni.2007.04.015
239.
Shemesh M., Addadi L., Geiger B. Surface microtopography modulates sealing zone development in osteoclasts cultured on bone. J. R. Soc. Interface. 2017;14:20160958.
Not in our library10.1098/rsif.2016.0958
240.
Nesbitt S.A., Horton M.A. Trafficking of matrix collagens through bone-resorbing osteoclasts. Science. 1997;276:266-269.
Not in our library10.1126/science.276.5310.266
241.
Salo J., Lehenkari P., Mulari M., Metsikko K., Vaananen H.K. Removal of osteoclast bone resorption products by transcytosis. Science. 1997;276:270-273.
Not in our library10.1126/science.276.5310.270
242.
Chabadel A., Bañon-Rodríguez I., Cluet D., Rudkin B.B., Wehrle-Haller B., Genot E., Jurdic P., Anton I.M., Saltel F. CD44 and beta3 integrin organize two functionally distinct actin-based domains in osteoclasts. Mol. Biol. Cell. 2007;18:4899-4910.
Not in our library10.1091/mbc.e07-04-0378
243.
Carman C.V. Mechanisms for transcellular diapedesis: Probing and pathfinding by ‘invadosome-like protrusions. J. Cell Sci. 2009;122:3025-3035.
Not in our library10.1242/jcs.047522
244.
Nakamura I., Duong L.T., Rodan S.B., Rodan G.A. Involvement of alpha(v)beta3 integrins in osteoclast function. J. Bone Miner. Metab. 2007;25:337-344.
Not in our library10.1007/s00774-007-0773-9
245.
Gardel M.L., Schneider I.C., Aratyn-Schaus Y., Waterman C.M. Mechanical integration of actin and adhesion dynamics in cell migration. Annu Rev. Cell Dev. Biol. 2010;26:315-333.
Not in our library10.1146/annurev.cellbio.011209.122036
246.
Bati G., Okvur D.P. Invadopodia: Proteolytic feet of cancer cells. Turk. J. Biol. 2014;38:740-747.
Not in our library10.3906/biy-1404-110
247.
Koçer G., Jonkheijm P. About Chemical Strategies to Fabricate Cell-Instructive Biointerfaces with Static and Dynamic Complexity. Adv. Healthc. Mater. 2018;7:e1701192.
Not in our library10.1002/adhm.201701192
248.
Buccione R., Orth J.D., McNiven M.A. Foot and mouth: Podosomes, invadopodia and circular dorsal ruffles. Nat. Rev. Mol. Cell Biol. 2004;5:647-657.
Not in our library10.1038/nrm1436
249.
Linder S., Aepfelbacher M. Podosomes: Adhesion hot-spots of invasive cells. Trends Cell Biol. 2003;13:376-385.
Not in our library10.1016/s0962-8924(03)00128-4
250.
Linder S., Wiesner C., Himmel M. Degrading devices: Invadosomes in proteolytic cell invasion. Annu. Rev. Cell Dev. Biol. 2011;27:185-211.
Not in our library10.1146/annurev-cellbio-092910-154216
251.
Murphy D.A., Courtneidge S.A. The ‘ins’ and ‘outs’ of podosomes and invadopodia: Characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 2011;12:413-426.
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Legerstee K., Geverts B., Slotman J.A., Houtsmuller A.B. Dynamics and distribution of paxillin, vinculin, zyxin and VASP depend on focal adhesion location and orientation. Sci. Rep. 2019;9:10460.
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Georgess D., Machuca-Gayet I., Blangy A., Jurdic P. Podosome organization drives osteoclast-mediated bone resorption. Cell Adh. Migr. 2014;8:191-204.
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Geblinger D., Addadi L., Geiger B. Nano-topography sensing by osteoclasts. J. Cell Sci. 2010;123:1503-1510.
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Kim D.H., Wirtz D. Focal adhesion size uniquely predicts cell migration. FASEB J. 2013;27:1351-1361.
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Veillat V., Spuul P., Daubon T., Egana I., Kramer I., Genot E. Podosomes: Multipurpose organelles? Int. J. Bio Chem. Cell Biol. 2015;65:52-60.
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Schachtner H., Calaminus S.D., Thomas S.G., Machesky L.M. Podosomes in adhesion, migration, mechanosensing and matrix remodeling. Cytoskeleton. 2013;70:572-589.
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Artym V.V., Matsumoto K., Mueller S.C., Yamada K.M. Dynamic membrane remodeling at invadopodia differentiates invadopodia from podosomes. Eur. J. Cell Biol. 2011;90:172-180.
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Zamir E., Katz B.Z., Aota S., Yamada K.M., Geiger B., Kam Z. Molecular diversity of cell-matrix adhesions. J. Cell Sci. 1999;112:1655-1669.
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Saltel F., Destaing O., Bard F., Eichert D., Jurdic P. Apatite-mediated actin dynamics in resorbing osteoclasts. Mol. Biol. Cell. 2004;15:5231-5241.
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261.
Pietras K., Ostman A. Hallmarks of cancer: Interactions with the tumor stroma. Exp. Cell Res. 2010;316:1324-1331.
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262.
Delon I., Brown N.H. Integrins and the actin cytoskeleton. Curr. Opin. Cell Biol. 2007;19:43-50.
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Geiger B., Bershadsky A., Pankov R., Yamada K.M. Transmembrane crosstalk between the extracellular matrix and the cytoskeleton. Nat. Rev. Mol. Cell Biol. 2001;2:793-805.
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Paolillo M., Galiazzo M.C., Daga A., Ciusani E., Serra M., Colombo L., Schinelli S. An RGD small-molecule integrin antagonist induces detachment-mediated anoikis in glioma cancer stem cells. Int. J. Oncol. 2018;53:2683-2694.
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Wu X., Cai J., Zuo Z., Li J. Collagen facilitates the colorectal cancer stemness and metastasis through an integrin/PI3K/AKT/Snail signaling pathway. Biomed. Pharmacother. 2019;114:108708.
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Hynes R.O. Integrins: Bidirectional, allosteric signaling machines. Cell. 2002;110:673-687.
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267.
Jin H., Jiang S., Wang R., Zhang Y., Dong J., Li Y. Mechanistic Insight Into the Roles of Integrins in Osteoarthritis. Front. Cell Dev. Biol. 2021;9:693484.
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268.
Michael M., Parsons M. New perspectives on integrin-dependent adhesions. Curr. Opin. Cell Biol. 2020;63:31-37.
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269.
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Luo B.H., Carman C.V., Springer T.A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 2007;25:619-647.
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Chen C., Manso A.M., Ross R.S. Talin and Kindlin as Integrin-Activating Proteins: Focus on the Heart. Pediatr. Cardiol. 2019;40:1401-1409.
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272.
Sun Z., Costell M., Fassler R. Integrin activation by talin, kindlin and mechanical forces. Nat. Cell Biol. 2019;21:25-31.
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273.
Takagi J., Petre B.M., Walz T., Springer T.A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002;110:599-611.
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Zhu J., Carman C.V., Kim M., Shimaoka M., Springer T.A., Luo B.H. Requirement of alpha and beta subunit transmembrane helix separation for integrin outside-in signaling. Blood. 2007;110:2475-2483.
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Samarzija I., Dekanic A., Humphries J.D., Paradzik M., Stojanovic N., Humphries M.J., Ambriovic-Ristov A. Integrin Crosstalk Contributes to the Complexity of Signalling and Unpredictable Cancer Cell Fates. Cancers. 2020;12:1910.
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Harburger D.S., Calderwood D.A. Integrin signalling at a glance. J. Cell Sci. 2009;122:159-163.
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Zhang X.A., Hemler M.E. Interaction of the integrin beta1 cytoplasmic domain with ICAP-1 protein. J. Biol. Chem. 1999;274:11-19.
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Zaidel-Bar R., Geiger B. The switchable integrin adhesome. J. Cell Sci. 2010;123:1385-1388.
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Horton E.R., Byron A., Askari J.A., Ng D.H.J., Millon-Fremillon A., Robertson J., Koper E.J., Paul N.R., Warwood S., Knight D., et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat. Cell Biol. 2015;17:1577-1587.
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280.
The integrin adhesome network at a glance · 2016
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281.
Wu C. Focal adhesion: A focal point in current cell biology and molecular medicine. Cell Adh. Migr. 2007;1:13-18.
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Lin S.S., Su Y.A., Chuang M.C., Liu Y.W. Probing invadosomes: Technologies for the analysis of invadosomes. FEBS J. 2021.
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283.
Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments · 2018
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284.
Mattila P.K., Lappalainen P. Filopodia: Molecular architecture and cellular functions. Nat. Rev. Mol. Cell Biol. 2008;9:446-454.
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285.
Small J.V., Stradal T., Vignal E., Rottner K. The lamellipodium: Where motility begins. Trends Cell Biol. 2002;12:112-120.
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286.
Itoh Y., Palmisano R., Anilkumar N., Nagase H., Miyawaki A., Seiki M. Dimerization of MT1-MMP during cellular invasion detected by fluorescence resonance energy transfer. Bio Chem. J. 2011;440:319-326.
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287.
Sato T., del Carmen Ovejero M., Hou P., Heegaard A.M., Kumegawa M., Foged N.T., Delaissé J.M. Identification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts. J. Cell Sci. 1997;110:589-596.
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288.
Itoh Y., Takamura A., Ito N., Maru Y., Sato H., Suenaga N., Aoki T., Seiki M. Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. EMBO J. 2001;20:4782-4793.
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289.
Mori H., Tomari T., Koshikawa N., Kajita M., Itoh Y., Sato H., Tojo H., Yana I., Seiki M. CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain. EMBO J. 2002;21:3949-3959.
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Suenaga N., Mori H., Itoh Y., Seiki M. CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase. Oncogene. 2005;24:859-868.
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291.
Actin-Based Cell Protrusion in a 3D Matrix · 2018
No notice
292.
Wolf K., Friedl P. Mapping proteolytic cancer cell-extracellular matrix interfaces. Clin. Exp. Metastasis. 2009;26:289-298.
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293.
Takino T., Saeki H., Miyamori H., Kudo T., Sato H. Inhibition of Membrane-Type 1 Matrix Metalloproteinase at Cell-Matrix Adhesions. Cancer Res. 2007;67:11621-11629.
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294.
Wolf K., Mazo I., Leung H., Engelke K., von Andrian U.H., Deryugina E.I., Strongin A.Y., Brocker E.B., Friedl P. Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 2003;160:267-277.
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295.
Galvez B.G., Matias-Roman S., Yanez-Mo M., Sanchez-Madrid F., Arroyo A.G. ECM regulates MT1-MMP localization with beta1 or alphavbeta3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells. J. Cell Biol. 2002;159:509-521.
Not in our library10.1083/jcb.200205026
296.
Puleo J.I., Parker S.S., Roman M.R., Watson A.W., Eliato K.R., Peng L., Saboda K., Roe D.J., Ros R., Gertler F.B., et al. Mechanosensing during directed cell migration requires dynamic actin polymerization at focal adhesions. J. Cell Biol. 2019;218:4215-4235.
Not in our library10.1083/jcb.201902101
297.
Wang Y., McNiven M.A. Invasive matrix degradation at focal adhesions occurs via protease recruitment by a FAK-p130Cas complex. J. Cell Biol. 2012;196:375-385.
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298.
Li X.Y., Ota I., Yana I., Sabeh F., Weiss S.J. Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase. Mol. Biol. Cell. 2008;19:3221-3323.
Not in our library10.1091/mbc.e08-01-0016
299.
Hotary K.B., Allen E.D., Brooks P.C., Datta N.S., Long M.W., Weiss S.J. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell. 2003;114:33-45.
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300.
Woskowicz A.M., Weaver S.A., Shitomi Y., Ito N., Itoh Y. MT-LOOP-dependent localization of membrane type I matrix metalloproteinase (MT1-MMP) to the cell adhesion complexes promotes cancer cell invasion. J. Biol. Chem. 2013;288:35126-35137.
Not in our library10.1074/jbc.m113.496067
301.
Geiger B., Yamada K.M. Molecular architecture and function of matrix adhesions. Cold Spring Harb. Perspect. Biol. 2011;3:a005033.
Not in our library10.1101/cshperspect.a005033
302.
Erdogan B., Ao M., White L.M., Means A.L., Brewer B.M., Yang L., Washington M.K., Shi C., Franco O.E., Weaver A.M., et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 2017;216:3799-3816.
Not in our library10.1083/jcb.201704053
303.
Friedl P., Wolf K. Proteolytic interstitial cell migration: A five-step process. Cancer Metastasis Rev. 2009;28:129-135.
Not in our library10.1007/s10555-008-9174-3
304.
Seano G., Primo L. Podosomes and invadopodia: Tools to breach vascular basement membrane. Cell Cycle. 2015;14:1370-1374.
Not in our library10.1080/15384101.2015.1026523
305.
Cox S., Rosten E., Monypenny J., Jovanovic-Talisman T., Burnette D.T., Lippincott-Schwartz J., Jones G.E., Heintzmann R. Bayesian localization microscopy reveals nanoscale podosome dynamics. Nat. Methods. 2011;9:195-200.
Not in our library10.1038/nmeth.1812
306.
Sharma V.P., Eddy R., Entenberg D., Kai M., Gertler F.B., Condeelis J. Tks5 and SHIP2 regulate invadopodium maturation, but not initiation, in breast carcinoma cells. Curr. Biol. 2013;23:2079-2089.
Not in our library10.1016/j.cub.2013.08.044
307.
Weaver A.M. Invadopodia. Curr. Biol. 2008;18:R362-R364.
Not in our library10.1016/j.cub.2008.02.028
308.
Gimona M., Buccione R., Courtneidge S.A., Linder S. Assembly and biological role of podosomes and invadopodia. Curr. Opin. Cell Biol. 2008;20:235-241.
Not in our library10.1016/j.ceb.2008.01.005
309.
Ostrowski P.P., Freeman S.A., Fairn G., Grinstein S. Dynamic Podosome-Like Structures in Nascent Phagosomes Are Coordinated by Phosphoinositides. Dev. Cell. 2019;50:397-410.e3.
Not in our library10.1016/j.devcel.2019.05.028
310.
Pacini S., Fazzi R., Montali M., Carnicelli V., Lazzarini E., Petrini M. Specific integrin expression is associated with podosome-like structures on mesodermal progenitor cells. Stem Cells Dev. 2013;22:1830-1838.
Not in our library10.1089/scd.2012.0423
311.
Rui Y.N., Chen Y., Guo Y., Bock C.E., Hagan J.P., Kim D.H., Xu Z. Podosome formation impairs endothelial barrier function by sequestering zonula occludens proteins. J. Cell Physiol. 2020;235:4655-4666.
Not in our library10.1002/jcp.29343
312.
Chuang M.C., Lin S.S., Ohniwa R.L., Lee G.H., Su Y.A., Chang Y.C., Tang M.J., Liu Y.W. Tks5 and Dynamin-2 enhance actin bundle rigidity in invadosomes to promote myoblast fusion. J. Cell Biol. 2019;218:1670-1685.
Not in our library10.1083/jcb.201809161
313.
Faust J.J., Balabiyev A., Heddleston J.M., Podolnikova N.P., Baluch D.P., Chew T.L., Ugarova T.P. An actin-based protrusion originating from a podosome-enriched region initiates macrophage fusion. Mol. Biol. Cell. 2019;30:2254-2267.
Not in our library10.1091/mbc.e19-01-0009
314.
Calle Y., Chou H.C., Thrasher A.J., Jones G.E. Wiskott-Aldrich syndrome protein and the cytoskeletal dynamics of dendritic cells. J. Pathol. 2004;204:460-469.
Not in our library10.1002/path.1651
315.
Panzer L., Trübe L., Klose M., Joosten B., Slotman J., Cambi A., Linder S. The formins FHOD1 and INF2 regulate inter-and intra-structural contractility of podosomes. J. Cell Sci. 2016;129:298-313.
Not in our library10.1242/jcs.177691
316.
Foxall E., Staszowska A., Hirvonen L.M., Georgouli M., Ciccioli M., Rimmer A., Williams L., Calle Y., Sanz-Moreno V., Cox S., et al. PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells. Cell Rep. 2019;29:3385-3393.e6.
Not in our library10.1016/j.celrep.2019.11.016
317.
Akisaka T., Yoshida H., Suzuki R., Takama K. Adhesion structures and their cytoskeleton-membrane interactions at podosomes of osteoclasts in culture. Cell Tissue Res. 2008;331:625-641.
Not in our library10.1007/s00441-007-0552-x
318.
Van den Dries K., Nahidiazar L., Slotman J.A., Meddens M.B.M., Pandzic E., Joosten B., Ansems M., Schouwstra J., Meijer A., Steen R., et al. Modular actin nano-architecture enables podosome protrusion and mechanosensing. Nat. Commun. 2019;10:5171.
Not in our library10.1038/s41467-019-13123-3
319.
Van den Dries K., Linder S., Maridonneau-Parini I., Poincloux R. Probing the mechanical landscape—New insights into podosome architecture and mechanics. J. Cell Sci. 2019;132:jcs236828.
Not in our library10.1242/jcs.236828
320.
Linder S. The matrix corroded: Podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 2007;17:107-117.
Not in our library10.1016/j.tcb.2007.01.002
321.
Cervero P., Wiesner C., Bouissou A., Poincloux R., Linder S. Lymphocyte-specific protein 1 regulates mechanosensory oscillation of podosomes and actin isoform-based actomyosin symmetry breaking. Nat. Commun. 2018;9:515.
Not in our library10.1038/s41467-018-02904-x
322.
Labernadie A., Thibault C., Vieu C., Maridonneau-Parini I., Charriere G.M. Dynamics of podosome stiffness revealed by atomic force microscopy. Proc. Natl. Acad. Sci. USA. 2010;107:21016-21021.
Not in our library10.1073/pnas.1007835107
323.
Collin O., Tracqui P., Stephanou A., Usson Y., Clement-Lacroix J., Planus E. Spatiotemporal dynamics of actin-rich adhesion microdomains: Influence of substrate flexibility. J. Cell Sci. 2006;119:1914-1925.
Not in our library10.1242/jcs.02838
324.
Bouissou A., Proag A., Bourg N., Pingris K., Cabriel C., Balor S., Mangeat T., Thibault C., Vieu C., Dupuis G., et al. Podosome Force Generation Machinery: A Local Balance between Protrusion at the Core and Traction at the Ring. ACS Nano. 2017;11:4028-4040.
Not in our library10.1021/acsnano.7b00622
325.
DNA mechanotechnology reveals that integrin receptors apply pN forces in podosomes on fluid substrates · 2019
Not checked
326.
Panciera T., Azzolin L., Cordenonsi M., Piccolo S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. 2017;18:758-770.
Not in our library10.1038/nrm.2017.87
327.
Tang Y., Rowe R.G., Botvinick E.L., Kurup A., Putnam A.J., Seiki M., Weaver V.M., Keller E.T., Goldstein S., Dai J., et al. MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis. Dev. Cell. 2013;25:402-416.
Not in our library10.1016/j.devcel.2013.04.011
328.
Torrino S., Roustan F.R., Kaminski L., Bertero T., Pisano S., Ambrosetti D., Dufies M., Uhler J.P., Lemichez E., Mettouchi A., et al. UBTD1 is a mechano-regulator controlling cancer aggressiveness. EMBO Rep. 2019;20:e46570.
Not in our library10.15252/embr.201846570
329.
Meddens M.B., Pandzic E., Slotman J.A., Guillet D., Joosten B., Mennens S., Paardekooper L.M., Houtsmuller A.B., van den Dries K., Wiseman P.W., et al. Actomyosin-dependent dynamic spatial patterns of cytoskeletal components drive mesoscale podosome organization. Nat. Commun. 2016;7:13127.
Not in our library10.1038/ncomms13127
330.
Revach O.Y., Weiner A., Rechav K., Sabanay I., Livne A., Geiger B. Mechanical interplay between invadopodia and the nucleus in cultured cancer cells. Sci. Rep. 2015;5:9466.
Not in our library10.1038/srep09466
331.
Cambi A., Chavrier P. Tissue remodeling by invadosomes. FAC Rev. 2021;10:39.
Not in our library10.12703/r/10-39
332.
Eddy R.J., Weidmann M.D., Sharma V.P., Condeelis J.S. Tumor Cell Invadopodia: Invasive Protrusions that Orchestrate Metastasis. Trends Cell Biol. 2017;27:595-607.
Not in our library10.1016/j.tcb.2017.03.003
333.
Oser M., Yamaguchi H., Mader C.C., Bravo-Cordero J.J., Arias M., Chen X., Desmarais V., van Rheenen J., Koleske A.J., Condeelis J. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J. Cell Biol. 2009;186:571-587.
Not in our library10.1083/jcb.200812176
334.
Gulvady A.C., Forsythe I.J., Turner C.E. Hic-5 regulates Src-induced invadopodia rosette formation and organization. Mol. Biol. Cell. 2019;30:1298-1313.
Not in our library10.1091/mbc.e18-10-0629
335.
The regulation of MMP targeting to invadopodia during cancer metastasis · 2015
No notice
336.
Monteiro P., Rossé C., Castro-Castro A., Irondelle M., Lagoutte E., Paul-Gilloteaux P., Desnos C., Formstecher E., Darchen F., Perrais D., et al. Endosomal WASH and exocyst complexes control exocytosis of MT1-MMP at invadopodia. J. Cell Biol. 2013;203:1063-1079.
Not in our library10.1083/jcb.201306162
337.
Marchesin V., Castro-Castro A., Lodillinsky C., Castagnino A., Cyrta J., Bonsang-Kitzis H., Fuhrmann L., Irondelle M., Infante E., Montagnac G., et al. ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. J. Cell Biol. 2015;211:339-358.
Not in our library10.1083/jcb.201506002
338.
Castagnino A., Castro-Castro A., Irondelle M., Guichard A., Lodillinsky C., Fuhrmann L., Vacher S., Agüera-González S., Zagryazhskaya-Masson A., Romao M., et al. Coronin 1C promotes triple-negative breast cancer invasiveness through regulation of MT1-MMP traffic and invadopodia function. Oncogene. 2018;37:6425-6441.
Not in our library10.1038/s41388-018-0422-x
339.
Sharma P., Parveen S., Shah L.V., Mukherjee M., Kalaidzidis Y., Kozielski A.J., Rosato R., Chang J.C., Datta S. SNX27-retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis. J. Cell Biol. 2020;219:e201812098.
Not in our library10.1083/jcb.201812098
340.
Beaty B.T., Sharma V.P., Bravo-Cordero J.J., Simpson M.A., Eddy R.J., Koleske A.J., Condeelis J. β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Mol. Biol. Cell. 2013;24:1661-1675.
Not in our library10.1091/mbc.e12-12-0908
341.
Nakahara H., Mueller S.C., Nomizu M., Yamada Y., Yeh Y., Chen W.T. Activation of beta1 integrin signaling stimulates tyrosine phosphorylation of p190RhoGAP and membrane-protrusive activities at invadopodia. J. Biol. Chem. 1998;273:9-12.
Not in our library10.1074/jbc.273.1.9
342.
Williams K.C., Coppolino M.G. SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion. J. Cell Sci. 2014;127:1712-1725.
Not in our library10.1242/jcs.134734
343.
Skalski M., Yi Q., Kean M.J., Myers D.W., Williams K.C., Burtnik A., Coppolino M.G. Lamellipodium extension and membrane ruffling require different SNARE-mediated trafficking pathways. BMC Cell Biol. 2010;11:62.
Not in our library10.1186/1471-2121-11-62
344.
Skalski M., Sharma N., Williams K., Kruspe A., Coppolino M.G. SNARE-mediated membrane traffic is required for focal adhesion kinase signaling and Src-regulated focal adhesion turnover. Biochim. Biophys. Acta. 2011;1813:148-158.
Not in our library10.1016/j.bbamcr.2010.09.008
345.
Kean M.J., Williams K.C., Skalski M., Myers D., Burtnik A., Foster D., Coppolino M.G. VAMP3, syntaxin-13 and SNAP23 are involved in secretion of matrix metalloproteinases, degradation of the extracellular matrix and cell invasion. J. Cell Sci. 2009;122:4089-4098.
Not in our library10.1242/jcs.052761
346.
Williams K.C., McNeilly R.E., Coppolino M.G. SNAP23, Syntaxin4, and vesicle-associated membrane protein 7 (VAMP7) mediate trafficking of membrane type 1-matrix metalloproteinase (MT1-MMP) during invadopodium formation and tumor cell invasion. Mol. Biol. Cell. 2014;25:2061-2070.
Not in our library10.1091/mbc.e13-10-0582
347.
Gorshtein G., Grafinger O., Coppolino M.G. Targeting SNARE-Mediated Vesicle Transport to Block Invadopodium-Based Cancer Cell Invasion. Front. Oncol. 2021;11:679955.
Not in our library10.3389/fonc.2021.679955
348.
Hoshino D., Kirkbride K.C., Costello K., Clark E.S., Sinha S., Grega-Larson N., Tyska M.J., Weaver A.M. Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep. 2013;5:1159-1168.
Not in our library10.1016/j.celrep.2013.10.050
349.
Hakulinen J., Sankkila L., Sugiyama N., Lehti K., Keski-Oja J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J. Cell Bio. Chem. 2008;105:1211-1218.
Not in our library10.1002/jcb.21923
350.
Meirson T., Gil-Henn H. Targeting invadopodia for blocking breast cancer metastasis. Drug Resist. Updat. 2018;39:1-17.
Not in our library10.1016/j.drup.2018.05.002
351.
Burger K.L., Learman B.S., Boucherle A.K., Sirintrapun S.J., Isom S., Diaz B., Courtneidge S.A., Seals D.F. Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. Prostate. 2014;74:134-148.
Not in our library10.1002/pros.22735
352.
Stylli S.S., Stacey T.T., Kaye A.H., Lock P. Prognostic significance of Tks5 expression in gliomas. J. Clin. Neuro Sci. 2012;19:436-442.
Not in our library10.1016/j.jocn.2011.11.013
353.
Li C.M., Chen G., Dayton T.L., Kim-Kiselak C., Hoersch S., Whittaker C.A., Bronson R.T., Beer D.G., Winslow M.M., Jacks T. Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma. Genes Dev. 2013;27:1557-1567.
Not in our library10.1101/gad.222745.113
354.
Eckert M.A., Lwin T.M., Chang A.T., Kim J., Danis E., Ohno-Machado L., Yang J. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011;19:372-386.
Not in our library10.1016/j.ccr.2011.01.036
355.
Rosenthal E.L., Matrisian L.M. Matrix metalloproteases in head and neck cancer. Head Neck. 2006;28:639-648.
Not in our library10.1002/hed.20365
356.
Bowden E.T., Barth M., Thomas D., Glazer R.I., Mueller S.C. An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Oncogene. 1999;18:4440-4449.
Not in our library10.1038/sj.onc.1202827
357.
Clark E.S., Whigham A.S., Yarbrough W.G., Weaver A.M. Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res. 2007;67:4227-4235.
Not in our library10.1158/0008-5472.can-06-3928
358.
Li Y., Tondravi M., Liu J., Smith E., Haudenschild C.C., Kaczmarek M., Zhan X. Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res. 2001;61:6906-6911.
Not in our library
359.
Chen W.T., Wang J.Y. Specialized surface protrusions of invasive cells, invadopodia and lamellipodia, have differential MT1-MMP, MMP-2, and TIMP-2 localization. Ann. N. Y. Acad. Sci. 1999;878:361-371.
Not in our library10.1111/j.1749-6632.1999.tb07695.x
360.
Mazzone M., Baldassarre M., Beznoussenko G., Giacchetti G., Cao J., Zucker S., Luini A., Buccione R. Intracellular processing and activation of membrane type 1 matrix metalloprotease depends on its partitioning into lipid domains. J. Cell Sci. 2004;117:6275-6287.
Not in our library10.1242/jcs.01563
361.
Nakahara H., Howard L., Thompson E.W., Sato H., Seiki M., Yeh Y., Chen W.T. Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc. Natl. Acad. Sci. USA. 1997;94:7959-7964.
Not in our library10.1073/pnas.94.15.7959
362.
Revach O.Y., Geiger B. The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion. Cell Adh. Migr. 2014;8:215-225.
Not in our library10.4161/cam.27842
363.
Smith J.M., Hedman A.C., Sacks D.B. IQGAPs choreograph cellular signaling from the membrane to the nucleus. Trends Cell Biol. 2015;25:171-184.
Not in our library10.1016/j.tcb.2014.12.005
364.
Li A., Dawson J.C., Forero-Vargas M., Spence H.J., Yu X., Konig I., Anderson K., Machesky L.M. The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion. Curr. Biol. 2010;20:339-345.
Not in our library10.1016/j.cub.2009.12.035
365.
Destaing O., Saltel F., Geminard J.C., Jurdic P., Bard F. Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein. Mol. Biol. Cell. 2003;14:407-416.
Not in our library10.1091/mbc.e02-07-0389
366.
Kumar S., Das A., Barai A., Sen S. MMP Secretion Rate and Inter-invadopodia Spacing Collectively Govern Cancer Invasiveness. Biophys. J. 2018;114:650-662.
Not in our library10.1016/j.bpj.2017.11.3777
367.
Bhuwania R., Cornfine S., Fang Z.Y., Kruger M., Luna E.J., Linder S. Supervillin couples myosin-dependent contractility to podosomes and enables their turnover. J. Cell Sci. 2012;125:2300-2314.
Not in our library10.1242/jcs.100032
368.
Patel A., Dash P.R. Formation of atypical podosomes in extravillous trophoblasts regulates extracellular matrix degradation. Eur. J. Cell Biol. 2012;91:171-179.
Not in our library10.1016/j.ejcb.2011.11.006
369.
Monsky W.L., Lin C.Y., Aoyama A., Kelly T., Akiyama S.K., Mueller S.C., Chen W.T. A potential marker protease of invasiveness, seprase, is localized on invadopodia of human malignant melanoma cells. Cancer Res. 1994;54:5702-5710.
Not in our library
370.
Yu X., Zech T., McDonald L., Gonzalez E.G., Li A., Macpherson I., Schwarz J.P., Spence H., Futó K., Timpson P., et al. N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. J. Cell Biol. 2012;199:527-544.
Not in our library10.1083/jcb.201203025
371.
Lohmer L.L., Kelley L.C., Hagedorn E.J., Sherwood D.R. Invadopodia and basement membrane invasion in vivo. Cell Adh. Migr. 2014;8:246-255.
Not in our library10.4161/cam.28406
372.
Eschenbruch J., Dreissen G., Springer R., Konrad J., Merkel R., Hoffmann B., Noetzel E. From Microspikes to Stress Fibers: Actin Remodeling in Breast Acini Drives Myosin II-Mediated Basement Membrane Invasion. Cells. 2021;10:1979.
Not in our library10.3390/cells10081979
373.
Parekh A., Weaver A.M. Regulation of invadopodia by mechanical signaling. Exp. Cell Res. 2016;343:89-95.
Not in our library10.1016/j.yexcr.2015.10.038
374.
Di Martino J., Henriet E., Ezzoukhry Z., Goetz J.G., Moreau V., Saltel F. The microenvironment controls invadosome plasticity. J. Cell Sci. 2016;129:1759-1768.
Not in our library10.1242/jcs.182329
375.
Beaty B.T., Condeelis J. Digging a little deeper: The stages of invadopodium formation and maturation. Eur. J. Cell Biol. 2014;93:438-444.
Not in our library10.1016/j.ejcb.2014.07.003
376.
Siqueira A.S., Pinto M.P., Cruz M.C., Smuczek B., Cruz K.S., Barbuto J.A., Hoshino D., Weaver A.M., Freitas V.M., Jaeger R.G. Laminin-111 peptide C16 regulates invadopodia activity of malignant cells through β1 integrin, Src and ERK 1/2. Oncotarget. 2016;7:47904-47917.
Not in our library10.18632/oncotarget.10062
377.
Seals D.F., Azucena E.F., Pass I., Tesfay L., Gordon R., Woodrow M., Resau J.H., Courtneidge S.A. The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell. 2005;7:155-165.
Not in our library10.1016/j.ccr.2005.01.006
378.
Naegeli K.M., Hastie E., Garde A., Wang Z., Keeley D.P., Gordon K.L., Pani A.M., Kelley L.C., Morrissey M.A., Chi Q., et al. Cell Invasion In Vivo via Rapid Exocytosis of a Transient Lysosome-Derived Membrane Domain. Dev. Cell. 2017;43:403-417.e10.
Not in our library10.1016/j.devcel.2017.10.024
379.
Kedziora K.M., Isogai T., Jalink K., Innocenti M. Invadosomes—Shaping actin networks to follow mechanical cues. Front. BioSci. 2016;21:1092-1117.
Not in our library10.2741/4444
380.
Pourfarhangi K.E., Bergman A., Gligorijevic B. ECM Cross-Linking Regulates Invadopodia Dynamics. Biophys. J. 2018;114:1455-1466.
Not in our library10.1016/j.bpj.2018.01.027
381.
Saha T., Gil-Henn H. Invadopodia, a Kingdom of Non-Receptor Tyrosine Kinases. Cells. 2021;10:2037.
Not in our library10.3390/cells10082037
382.
Chan K.T., Cortesio C.L., Huttenlocher A. FAK alters invadopodia and focal adhesion composition and dynamics to regulate breast cancer invasion. J. Cell Biol. 2009;185:357-370.
Not in our library10.1083/jcb.200809110
383.
Genna A., Lapetina S., Lukic N., Twafra S., Meirson T., Sharma V.P., Condeelis J.S., Gil-Henn H. Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells. J. Cell Biol. 2018;217:375-395.
Not in our library10.1083/jcb.201702184
384.
Oikawa T., Oyama M., Kozuka-Hata H., Uehara S., Udagawa N., Saya H., Matsuo K. Tks5-dependent formation of circumferential podosomes/invadopodia mediates cell-cell fusion. J. Cell Biol. 2012;197:553-568.
Not in our library10.1083/jcb.201111116
385.
Stylli S.S., Stacey T.T., Verhagen A.M., Xu S.S., Pass I., Courtneidge S.A., Lock P. Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. J. Cell Sci. 2009;122:2727-2740.
Not in our library10.1242/jcs.046680
386.
Mader C.C., Oser M., Magalhaes M.A., Bravo-Cordero J.J., Condeelis J., Koleske A.J., Gil-Henn H. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res. 2011;71:1730-1741.
Not in our library10.1158/0008-5472.can-10-1432
387.
Gil-Henn H., Patsialou A., Wang Y., Warren M.S., Condeelis J.S., Koleske A.J. Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo. Oncogene. 2013;32:2622-2630.
Not in our library10.1038/onc.2012.284
388.
Gasparski A.N., Wilson J.T., Banerjee A., Beningo K.A. The Role of PAK1 in the Maturation of Invadopodia During Transient Mechanical Stimulation. Front. Cell Dev. Biol. 2019;7:269.
Not in our library10.3389/fcell.2019.00269
389.
Kang H., Hong Z., Zhong M., Klomp J., Bayless K.J., Mehta D., Karginov A.V., Hu G., Malik A.B. Piezo1 mediates angiogenesis through activation of MT1-MMP signaling. Am. J. Physiol. Cell Physiol. 2019;316:C92-C103.
Not in our library10.1152/ajpcell.00346.2018
390.
Li C., Rezania S., Kammerer S., Sokolowski A., Devaney T., Gorischek A., Jahn S., Hackl H., Groschner K., Windpassinger C., et al. Piezo1 forms mechanosensitive ion channels in the human MCF-7 breast cancer cell line. Sci. Rep. 2015;5:8364.
Not in our library10.1038/srep08364
391.
Yang X.N., Lu Y.P., Liu J.J., Huang J.K., Liu Y.P., Xiao C.X., Jazag A., Ren J.L., Guleng B. Piezo1 is as a novel trefoil factor family 1 binding protein that promotes gastric cancer cell mobility in vitro. Dig. Dis. Sci. 2014;59:1428-1435.
Not in our library10.1007/s10620-014-3044-3
392.
Leong H.S., Robertson A.E., Stoletov K., Leith S.J., Chin C.A., Chien A.E., Hague M.N., Ablack A., Carmine-Simmen K., McPherson V.A., et al. Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep. 2014;8:1558-1570.
Not in our library10.1016/j.celrep.2014.07.050
393.
Kumari A., Pineau J., Saez P.J., Maurin M., Lankar D., San Roman M., Hennig K., Boura V.F., Voituriez R., Karlsson M.C.I., et al. Actomyosin-driven force patterning controls endocytosis at the immune synapse. Nat. Commun. 2019;10:2870.
Not in our library10.1038/s41467-019-10751-7
394.
Pettmann J., Santos A.M., Dushek O., Davis S.J. Membrane Ultrastructure and T Cell Activation. Front. Immunol. 2018;9:2152.
Not in our library10.3389/fimmu.2018.02152
395.
Juin A., Billottet C., Moreau V., Destaing O., Albiges-Rizo C., Rosenbaum J., Génot E., Saltel F. Physiological type I collagen organization induces the formation of a novel class of linear invadosomes. Mol. Biol. Cell. 2012;23:297-309.
Not in our library10.1091/mbc.e11-07-0594
396.
Juin A., Di Martino J., Leitinger B., Henriet E., Gary A.S., Paysan L., Bomo J., Baffet G., Gauthier-Rouvière C., Rosenbaum J., et al. Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway. J. Cell Biol. 2014;207:517-533.
Not in our library10.1083/jcb.201404079
397.
The Architecture of the Adhesive Apparatus of Cultured Osteoclasts: From Podosome Formation to Sealing Zone Assembly · 2007
No notice
398.
Luxenburg C., Addadi L., Geiger B. The molecular dynamics of osteoclast adhesions. Eur. J. Cell Biol. 2006;85:203-211.
Not in our library10.1016/j.ejcb.2005.11.002
399.
Luxenburg C., Parsons J.T., Addadi L., Geiger B. Involvement of the Src-cortactin pathway in podosome formation and turnover during polarization of cultured osteoclasts. J. Cell Sci. 2006;119:4878-4888.
Not in our library10.1242/jcs.03271
400.
Liang H.P.H., Xu J., Xue M., Jackson C. Matrix metalloproteinases in bone development and pathology: Current knowledge and potential clinical utility. Met. Med. 2016;3:93-102.
Not in our library10.2147/mnm.s92187
401.
Zhu L., Tang Y., Li X.Y., Keller E.T., Yang J., Cho J.S., Feinberg T.Y., Weiss S.J. Osteoclast-mediated bone resorption is controlled by a compensatory network of secreted and membrane-tethered metalloproteinases. Sci. Transl. Med. 2020;12.
Not in our library10.1126/scitranslmed.aaw6143
402.
Karamanos N.K., Theocharis A.D., Piperigkou Z., Manou D., Passi A., Skandalis S.S., Vynios D.H., Orian-Rousseau V., Ricard-Blum S., Schmelzer C.E.H., et al. A guide to the composition and functions of the extracellular matrix. FEBS J. 2021.
Not in our library10.1111/febs.15776
403.
Hu Y., Lou J., Jin Z., Yang X., Shan W., Du Q., Liao Q., Xu J., Xie R. Advances in research on the regulatory mechanism of NHE1 in tumors. Oncol. Lett. 2021;21:273.
Not in our library10.3892/ol.2021.12534
404.
Bravo-Cordero J.J., Magalhaes M.A., Eddy R.J., Hodgson L., Condeelis J. Functions of cofilin in cell locomotion and invasion. Nat. Rev. Mol. Cell Biol. 2013;14:405-415.
Not in our library10.1038/nrm3609
405.
Matsubara T., Addison W.N., Kokabu S., Neff L., Horne W., Gori F., Baron R. Characterization of unique functionalities in c-Src domains required for osteoclast podosome belt formation. J. Biol. Chem. 2021;296:100790.
Not in our library10.1016/j.jbc.2021.100790
406.
Denais C.M., Gilbert R.M., Isermann P., McGregor A.L., te Lindert M., Weigelin B., Davidson P.M., Friedl P., Wolf K., Lammerding J. Nuclear envelope rupture and repair during cancer cell migration. Science. 2016;352:353-358.
Not in our library10.1126/science.aad7297
407.
Friedl P., Wolf K., Lammerding J. Nuclear mechanics during cell migration. Curr. Opin. Cell Biol. 2011;23:55-64.
Not in our library10.1016/j.ceb.2010.10.015
408.
Wolf K., Friedl P. Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol. 2011;21:736-744.
Not in our library10.1016/j.tcb.2011.09.006
409.
Elwakeel E., Weigert A. Breast Cancer CAFs: Spectrum of Phenotypes and Promising Targeting Avenues. Int. J. Mol. Sci. 2021;22:11636.
Not in our library10.3390/ijms222111636
410.
Dvorak H.F. Tumors: Wounds that do not heal-redux. Cancer Immunol. Res. 2015;3:1-11.
Not in our library10.1158/2326-6066.cir-14-0209
411.
Dvorak H.F. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986;315:1650-1659.
Not in our library10.1056/nejm198612253152606
412.
Obermann W.M.J., Brockhaus K., Eble J.A. Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment. Front. Cell Dev. Biol. 2021;9:674553.
Not in our library10.3389/fcell.2021.674553
413.
Tian C., Clauser K.R., Öhlund D., Rickelt S., Huang Y., Gupta M., Mani D.R., Carr S.A., Tuveson D.A., Hynes R.O. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc. Natl. Acad. Sci. USA. 2019;116:19609-19618.
Not in our library10.1073/pnas.1908626116
414.
Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016;16:582-598.
Not in our library10.1038/nrc.2016.73
415.
A framework for advancing our understanding of cancer-associated fibroblasts · 2020
No notice
416.
Hirata E., Sahai E. Tumor Microenvironment and Differential Responses to Therapy. Cold Spring Harb. Perspect. Med. 2017;7:a026781.
Not in our library10.1101/cshperspect.a026781
417.
The role of stromal cancer-associated fibroblasts in pancreatic cancer · 2017
No notice
418.
Gajewski T.F., Schreiber H., Fu Y.X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 2013;14:1014-1022.
Not in our library10.1038/ni.2703
419.
Otranto M., Sarrazy V., Bonté F., Hinz B., Gabbiani G., Desmoulière A. The role of the myofibroblast in tumor stroma remodeling. Cell Adh. Migr. 2012;6:203-219.
Not in our library10.4161/cam.20377
420.
Mueller M.M., Fusenig N.E. Friends or foes-bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer. 2004;4:839-849.
Not in our library10.1038/nrc1477
421.
Mantovani A., Sozzani S., Locati M., Allavena P., Sica A. Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549-555.
Not in our library10.1016/s1471-4906(02)02302-5
422.
Roomi M.W., Kalinovsky T., Rath M., Niedzwiecki A. Modulation of MMP-2 and MMP-9 secretion by cytokines, inducers and inhibitors in human glioblastoma T-98G cells. Oncol. Rep. 2017;37:1907-1913.
Not in our library10.3892/or.2017.5391
423.
IL-1β-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9 · 2014
No notice
424.
Lee E.J., Park S.S., Kim W.J., Moon S.K. IL-5-induced migration via ERK1/2-mediated MMP-9 expression by inducing activation of NF-κB in HT1376 cells. Oncol. Rep. 2012;28:1084-1090.
Not in our library10.3892/or.2012.1857
425.
Lee E.J., Lee S.J., Kim S., Cho S.C., Choi Y.H., Kim W.J., Moon S.K. Interleukin-5 enhances the migration and invasion of bladder cancer cells via ERK1/2-mediated MMP-9/NF-kappaB/AP-1 pathway: Involvement of the p21WAF1 expression. Cell Signal. 2013;25:2025-2038.
Not in our library10.1016/j.cellsig.2013.06.004
426.
Ji Y., Yang X., Li J., Lu Z., Li X., Yu J., Li N. IL-22 promotes the migration and invasion of gastric cancer cells via IL-22R1/AKT/MMP-9 signaling. Int. J. Clin. Exp. Pathol. 2014;7:3694-3703.
Not in our library
427.
Fukui H., Zhang X., Sun C., Hara K., Kikuchi S., Yamasaki T., Kondo T., Tomita T., Oshima T., Watari J., et al. IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling. Br. J. Cancer. 2014;111:763-771.
Not in our library10.1038/bjc.2014.336
428.
Gjorgjevski M., Hannen R., Carl B., Li Y., Landmann E., Buchholz M., Bartsch J.W., Nimsky C. Molecular profiling of the tumor microenvironment in glioblastoma patients: Correlation of microglia/macrophage polarization state with metalloprotease expression profiles and survival. Biosci. Rep. 2019;39:BSR20182361.
Not in our library10.1042/bsr20182361
429.
Chen W., Xia T., Wang D., Huang B., Zhao P., Wang J., Qu X., Li X. Human astrocytes secrete IL-6 to promote glioma migration and invasion through upregulation of cytomembrane MMP14. Oncotarget. 2016;7:62425-62438.
Not in our library10.18632/oncotarget.11515
430.
Fingleton B. Matrix metalloproteinases as regulators of inflammatory processes. Biochim. Biophys. Acta Mol. Cell Res. 2017;1864 11 Pt A:2036-2042.
Not in our library10.1016/j.bbamcr.2017.05.010
431.
Aguirre A., Blázquez-Prieto J., Amado-Rodriguez L., López-Alonso I., Batalla-Solís E., González-López A., Sánchez-Pérez M., Mayoral-Garcia C., Gutiérrez-Fernández A., Albaiceta G.M. Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia. J. Mol. Med. 2017;95:487-497.
Not in our library10.1007/s00109-017-1510-z
432.
Greenlee K.J., Corry D.B., Engler D.A., Matsunami R.K., Tessier P., Cook R.G., Werb Z., Kheradmand F. Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation. J. Immunol. 2006;177:7312-7321.
Not in our library10.4049/jimmunol.177.10.7312
433.
Sithu S.D., English W.R., Olson P., Krubasik D., Baker A.H., Murphy G., D’Souza S.E. Membrane-type 1-matrix metalloproteinase regulates intracellular adhesion molecule-1 (ICAM-1)-mediated monocyte transmigration. J. Biol. Chem. 2007;282:25010-25019.
Not in our library10.1074/jbc.m611273200
434.
Salnikov A.V., Iversen V.V., Koisti M., Sundberg C., Johansson L., Stuhr L.B., Sjoquist M., Ahlstrom H., Reed R.K., Rubin K. Lowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy. FASEB J. 2003;17:1756-1758.
Not in our library10.1096/fj.02-1201fje
435.
Purkayastha P., Jaiswal M.K., Lele T.P. Molecular cancer cell responses to solid compressive stress and interstitial fluid pressure. Cytoskeleton. 2021;78:312-322.
Not in our library10.1002/cm.21680
436.
Wang J., Boddupalli A., Koelbl J., Nam D.H., Ge X., Bratlie K.M., Schneider I.C. Degradation and Remodeling of Epitaxially Grown Collagen Fibrils. Cell Mol. Bioeng. 2019;12:69-84.
Not in our library10.1007/s12195-018-0547-6
437.
Van Doren S.R. Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol. 2015;44–46:224-231.
Not in our library10.1016/j.matbio.2015.01.005
438.
Fields G.B. Biophysical studies of matrix metalloproteinase/triple-helix complexes. Adv. Protein Chem. Struct. Biol. 2014;97:37-48.
Not in our library10.1016/bs.apcsb.2014.09.001
439.
Ricard-Blum S. The collagen family. Cold Spring Harb. Perspect. Biol. 2011;3:a004978.
Not in our library10.1101/cshperspect.a004978
440.
Shaping Up the Tumor Microenvironment With Cellular Fibronectin · 2020
No notice
441.
Thakur R., Mishra D.P. Matrix reloaded: CCN, tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities. Pharmacol. Ther. 2016;168:61-74.
Not in our library10.1016/j.pharmthera.2016.09.002
442.
Schaefer L., Tredup C., Gubbiotti M.A., Iozzo R.V. Proteoglycan neofunctions: Regulation of inflammation and autophagy in cancer biology. FEBS J. 2017;284:10-26.
Not in our library10.1111/febs.13963
443.
Sofeu Feugaing D.D., Gotte M., Viola M. More than matrix: The multifaceted role of decorin in cancer. Eur. J. Cell Biol. 2013;92:1-11.
Not in our library10.1016/j.ejcb.2012.08.004
444.
Yoshida T., Akatsuka T., Imanaka-Yoshida K. Tenascin-C and integrins in cancer. Cell Adh. Migr. 2015;9:96-104.
Not in our library10.1080/19336918.2015.1008332
445.
Brellier F., Martina E., Degen M., Heuzé-Vourc’h N., Petit A., Kryza T., Courty Y., Terracciano L., Ruiz C., Chiquet-Ehrismann R. Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors. BMC Clin. Pathol. 2012;12:14.
Not in our library10.1186/1472-6890-12-14
446.
Chiquet-Ehrismann R., Hagios C., Matsumoto K. The tenascin gene family. Perspect. Dev. NeuroBiol. 1994;2:3-7.
Not in our library
447.
Bellahcène A., Castronovo V., Ogbureke K.U., Fisher L.W., Fedarko N.S. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): Multifunctional proteins in cancer. Nat. Rev. Cancer. 2008;8:212-226.
Not in our library10.1038/nrc2345
448.
Kamili N.A., Arthur C.M., Gerner-Smidt C., Tafesse E., Blenda A., Dias-Baruffi M., Stowell S.R. Key regulators of galectin-glycan interactions. Proteomics. 2016;16:3111-3125.
Not in our library10.1002/pmic.201600116
449.
Naschberger E., Liebl A., Schellerer V.S., Schütz M., Britzen-Laurent N., Kölbel P., Schaal U., Haep L., Regensburger D., Wittmann T., et al. Matricellular protein SPARCL1 regulates tumor microenvironment-dependent endothelial cell heterogeneity in colorectal carcinoma. J. Clin. Investig. 2016;126:4187-4204.
Not in our library10.1172/jci78260
450.
Roberts D.D., Kaur S., Isenberg J.S. Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer. Antioxid. Redox Signal. 2017;27:874-911.
Not in our library10.1089/ars.2017.7140
451.
Periostin: A Matricellular Protein With Multiple Functions in Cancer Development and Progression · 2018
No notice
452.
Vincent K.M., Postovit L.M. Matricellular proteins in cancer: A focus on secreted Frizzled-related proteins. J. Cell Commun. Signal. 2018;12:103-112.
Not in our library10.1007/s12079-017-0398-2
453.
Tucker R.P., Degen M. The Expression and Possible Functions of Tenascin-W During Development and Disease. Front. Cell Dev. Biol. 2019;7:53.
Not in our library10.3389/fcell.2019.00053
454.
Ong C.H., Tham C.L., Harith H.H., Firdaus N., Israf D.A. TGF-beta-induced fibrosis: A review on the underlying mechanism and potential therapeutic strategies. Eur. J. Pharmacol. 2021;911:174510.
Not in our library10.1016/j.ejphar.2021.174510
455.
Kong W., Lyu C., Liao H., Du Y. Collagen crosslinking: Effect on structure, mechanics and fibrosis progression. Biomed. Mater. 2021;16:062005.
Not in our library10.1088/1748-605x/ac2b79
456.
Setargew Y.F.I., Wyllie K., Grant R.D., Chitty J.L., Cox T.R. Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours. Cancers. 2021;13:491.
Not in our library10.3390/cancers13030491
457.
Tempest R., Guarnerio S., Maani R., Cooper J., Peake N. The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment. Cancers. 2021;13:2788.
Not in our library10.3390/cancers13112788
458.
Schenk S., Hintermann E., Bilban M., Koshikawa N., Hojilla C., Khokha R., Quaranta V. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J. Cell Biol. 2003;161:197-209.
Not in our library10.1083/jcb.200208145
459.
Gilles C., Polette M., Coraux C., Tournier J.M., Meneguzzi G., Munaut C., Volders L., Rousselle P., Birembaut P., Foidart J.M. Contribution of MT1-MMP and of human laminin-5 gamma2 chain degradation to mammary epithelial cell migration. J. Cell Sci. 2001;114:2967-2976.
Not in our library10.1242/jcs.114.16.2967
460.
Koshikawa N., Giannelli G., Cirulli V., Miyazaki K., Quaranta V. Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J. Cell Biol. 2000;148:615-624.
Not in our library10.1083/jcb.148.3.615
461.
Theocharis A.D., Manou D., Karamanos N.K. The extracellular matrix as a multitasking player in disease. FEBS J. 2019;286:2830-2869.
Not in our library10.1111/febs.14818
462.
Ji K., Mayernik L., Moin K., Sloane B.F. Acidosis and proteolysis in the tumor microenvironment. Cancer Metastasis Rev. 2019;38:103-112.
Not in our library10.1007/s10555-019-09796-3
463.
Greco M.R., Antelmi E., Busco G., Guerra L., Rubino R., Casavola V., Reshkin S.J., Cardone R.A. Protease activity at invadopodial focal digestive areas is dependent on NHE1-driven acidic pHe. Oncol. Rep. 2014;31:940-946.
Not in our library10.3892/or.2013.2923
464.
Lin Y., Chang G., Wang J., Jin W., Wang L., Li H., Ma L., Li Q., Pang T. NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP. Exp. Cell Res. 2011;317:2031-2040.
Not in our library10.1016/j.yexcr.2011.05.026
465.
Greco M.R., Moro L., Forciniti S., Alfarouk K., Cannone S., Cardone R.A., Reshkin S.J. Integrin-Linked Kinase Links Integrin Activation to Invadopodia Function and Invasion via the p(T567)-Ezrin/NHERF1/NHE1 Pathway. Int. J. Mol. Sci. 2021;22:2162.
Not in our library10.3390/ijms22042162
466.
Collagen reorganization at the tumor-stromal interface facilitates local invasion · 2006
No notice
467.
Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., Fong S.F., Csiszar K., Giaccia A., Weninger W., et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139:891-906.
Not in our library10.1016/j.cell.2009.10.027
468.
Van Helvert S., Storm C., Friedl P. Mechanoreciprocity in cell migration. Nat. Cell Biol. 2018;20:8-20.
Not in our library10.1038/s41556-017-0012-0
469.
Malandrino A., Mak M., Kamm R.D., Moeendarbary E. Complex mechanics of the heterogeneous extracellular matrix in cancer. Extreme Mech. Lett. 2018;21:25-34.
Not in our library10.1016/j.eml.2018.02.003
470.
Cellular Mechanotransduction: From Tension to Function · 2018
No notice
471.
Kapoor A., Chen C.G., Iozzo R.V. Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells. J. Biol. Chem. 2020;295:6344-6356.
Not in our library10.1074/jbc.ra120.012525
472.
Siegel G., Malmsten M., Ermilov E. Anionic biopolyelectrolytes of the syndecan/perlecan superfamily: Physicochemical properties and medical significance. Adv. Colloid Interface Sci. 2014;205:275-318.
Not in our library10.1016/j.cis.2014.01.009
473.
Cork S.M., Kaur B., Devi N.S., Cooper L., Saltz J.H., Sandberg E.M., Kaluz S., Van Meir E.G. A proprotein convertase/MMP-14 proteolytic cascade releases a novel 40 kDa vasculostatin from tumor suppressor BAI1. Oncogene. 2012;31:5144-5152.
Not in our library10.1038/onc.2012.1
474.
Pasco S., Han J., Gillery P., Bellon G., Maquart F.X., Borel J.P., Kefalides N.A., Monboisse J.C. A specific sequence of the noncollagenous domain of the alpha3(IV) chain of type IV collagen inhibits expression and activation of matrix metalloproteinases by tumor cells. Cancer Res. 2000;60:467-473.
Not in our library
475.
Taylor K.R., Trowbridge J.M., Rudisill J.A., Termeer C.C., Simon J.C., Gallo R.L. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J. Biol. Chem. 2004;279:17079-17084.
Not in our library10.1074/jbc.m310859200
476.
Voelcker V., Gebhardt C., Averbeck M., Saalbach A., Wolf V., Weih F., Sleeman J., Anderegg U., Simon J. Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4. Exp. Dermatol. 2008;17:100-107.
Not in our library10.1111/j.1600-0625.2007.00638.x
477.
Hadler-Olsen E., Winberg J.O., Uhlin-Hansen L. Matrix metalloproteinases in cancer: Their value as diagnostic and prognostic markers and therapeutic targets. Tumour. Biol. 2013;34:2041-2051.
Not in our library10.1007/s13277-013-0842-8
478.
Yao Q., Kou L., Tu Y., Zhu L. MMP-Responsive ‘Smart’ Drug Delivery and Tumor Targeting. Trends Pharmacol. Sci. 2018;39:766-781.
Not in our library10.1016/j.tips.2018.06.003
479.
Vandenbroucke R.E., Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat. Rev. Drug Discov. 2014;13:904-927.
Not in our library10.1038/nrd4390
480.
Winer A., Adams S., Mignatti P. Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes. Mol. Cancer Ther. 2018;17:1147-1155.
Not in our library10.1158/1535-7163.mct-17-0646
481.
MMpI: A WideRange of Available Compounds of Matrix Metalloproteinase Inhibitors. · 2016
Not checked
482.
BT1718 in Patients with Advanced Solid Tumours. 3 April 2018 (Cited 29 November 2021), 1 p. ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US), 12 Nov 2020. Identifier: NCT03486730.
Not in our library
483.
Concepts of extracellular matrix remodelling in tumour progression and metastasis · 2020
No notice
484.
Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics · 2020
No notice
485.
The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma · 2019
No notice
486.
Kaimal R., Aljumaily R., Tressel S.L., Pradhan R.V., Covic L., Kuliopulos A., Zarwan C., Kim Y.B., Sharifi S., Agarwal A. Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer. Cancer Res. 2013;73:2457-2467.
Not in our library10.1158/0008-5472.can-12-1426
487.
Stoletov K., Lewis J.D. Invadopodia: A new therapeutic target to block cancer metastasis. Expert Rev. Anticancer Ther. 2015;15:733-735.
Not in our library10.1586/14737140.2015.1058711
488.
Ngan E., Stoletov K., Smith H.W., Common J., Muller W.J., Lewis J.D., Siegel P.M. LPP is a Src substrate required for invadopodia formation and efficient breast cancer lung metastasis. Nat. Commun. 2017;8:15059.
Not in our library10.1038/ncomms15059
489.
Sutoh Yoneyama M., Hatakeyama S., Habuchi T., Inoue T., Nakamura T., Funyu T., Wiche G., Ohyama C., Tsuboi S. Vimentin intermediate filament and plectin provide a scaffold for invadopodia, facilitating cancer cell invasion and extravasation for metastasis. Eur. J. Cell Biol. 2014;93:157-169.
Not in our library10.1016/j.ejcb.2014.03.002
490.
Gligorijevic B., Wyckoff J., Yamaguchi H., Wang Y., Roussos E.T., Condeelis J. N-WASP-mediated invadopodium formation is involved in intravasation and lung metastasis of mammary tumors. J. Cell Sci. 2012;125:724-734.
Not in our library10.1242/jcs.092726
491.
Blouw B., Patel M., Iizuka S., Abdullah C., You W.K., Huang X., Li J.L., Diaz B., Stallcup W.B., Courtneidge S.A. The invadopodia scaffold protein Tks5 is required for the growth of human breast cancer cells in vitro and in vivo. PLoS ONE. 2015;10:e0121003.
Not in our library10.1371/journal.pone.0121003
492.
Cathcart J., Pulkoski-Gross A., Cao J. Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas. Genes Dis. 2015;2:26-34.
Not in our library10.1016/j.gendis.2014.12.002
493.
Meirson T., Genna A., Lukic N., Makhnii T., Alter J., Sharma V.P., Wang Y., Samson A.O., Condeelis J.S., Gil-Henn H. Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors. Oncotarget. 2018;9:22158-22183.
Not in our library10.18632/oncotarget.25243
494.
Ammer A.G., Kelley L.C., Hayes K.E., Evans J.V., Lopez-Skinner L.A., Martin K.H., Frederick B., Rothschild B.L., Raben D., Elvin P., et al. Saracatinib Impairs Head and Neck Squamous Cell Carcinoma Invasion by Disrupting Invadopodia Function. J. Cancer Sci. Ther. 2009;1:52-61.
Not in our library10.4172/1948-5956.1000009
495.
Quintavalle M., Elia L., Price J.H., Heynen-Genel S., Courtneidge S.A. A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion. Sci. Signal. 2011;4:ra49.
Not in our library10.1126/scisignal.2002032
496.
Karamanos N.K., Piperigkou Z., Passi A., Gotte M., Rousselle P., Vlodavsky I. Extracellular matrix-based cancer targeting. Trends Mol. Med. 2021;27:1000-1013.
Not in our library10.1016/j.molmed.2021.07.009
497.
Xiao Y., Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol. Ther. 2021;221:107753.
Not in our library10.1016/j.pharmthera.2020.107753
498.
Sheridan C. Pancreatic cancer provides testbed for first mechanotherapeutics. Nat. Biotechnol. 2019;37:829-831.
Not in our library10.1038/d41587-019-00019-2
499.
Abdollahiyan P., Oroojalian F., Baradaran B., de la Guardia M., Mokhtarzadeh A. Advanced mechanotherapy: Biotensegrity for governing metastatic tumor cell fate via modulating the extracellular matrix. J. Control. Release. 2021;335:596-618.
Not in our library10.1016/j.jconrel.2021.06.002
500.
Pietraszek K., Chatron-Colliet A., Brézillon S., Perreau C., Jakubiak-Augustyn A., Krotkiewski H., Maquart F.X., Wegrowski Y. Lumican: A new inhibitor of matrix metalloproteinase-14 activity. FEBS Lett. 2014;588:4319-4324.
Not in our library10.1016/j.febslet.2014.09.040
501.
Appunni S., Rubens M., Ramamoorthy V., Anand V., Khandelwal M., Saxena A., McGranaghan P., Odia Y., Kotecha R., Sharma A. Lumican, pro-tumorigenic or anti-tumorigenic: A conundrum. Clin. Chim Acta. 2021;514:1-7.
Not in our library10.1016/j.cca.2020.12.011
502.
Nguyen M.D., Kang K.A. MMP-14 Triggered Fluorescence Contrast Agent. Adv. Exp. Med. Biol. 2016;923:413-419.
Not in our library10.1007/978-3-319-38810-6_54
503.
Zhu L., Zhang F., Ma Y., Liu G., Kim K., Fang X., Lee S., Chen X. In vivo optical imaging of membrane-type matrix metalloproteinase (MT-MMP) activity. Mol. Pharm. 2011;8:2331-2338.
Not in our library10.1021/mp2002297
504.
Lee H., Kim Y.P. Fluorescent and Bioluminescent Nanoprobes for In Vitro and In Vivo Detection of Matrix Metalloproteinase Activity. BMB Rep. 2015;48:313-318.
Not in our library10.5483/bmbrep.2015.48.6.054
505.
Jeffrey E.J., Crawford B.D. The epitope-mediated MMP activation assay: Detection and quantification of the activation of Mmp2 in vivo in the zebrafish embryo. Histochem. Chem. Cell Biol. 2018;149:277-286.
Not in our library10.1007/s00418-018-1634-4
506.
Sun L., Xie S., Ji X., Zhang J., Wang D., Lee S.J., Lee H., He H., Yang V.C. MMP-2-responsive fluorescent nanoprobes for enhanced selectivity of tumor cell uptake and imaging. Biomater. Sci. 2018;6:2619-2626.
Not in our library10.1039/c8bm00593a

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