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The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer

Luying He, Qianming Kang, Ka Iong Chan and 3 more

Frontiers in Immunology · 2023 · Review · CC BY

doi:10.3389/fimmu.2022.1093990

Abstract

Matrix metalloproteinases (MMPs) are an important class of enzymes in the body that function through the extracellular matrix (ECM). They are involved in diverse pathophysiological processes, such as tumor invasion and metastasis, cardiovascular diseases, arthritis, periodontal disease, osteogenesis imperfecta, and diseases of the central nervous system. MMPs participate in the occurrence and development of numerous cancers and are closely related to immunity. In the present study, we review the immunomodulatory role of MMPs in colitis-associated cancer (CAC) and discuss relevant clinical applications. We analyze more than 300 pharmacological studies retrieved from PubMed and the Web of Science, related to MMPs, cancer, colitis, CAC, and immunomodulation. Key MMPs that interfere with pathological processes in CAC such as MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13, as well as their corresponding mechanisms are elaborated. MMPs are involved in cell proliferation, cell differentiation, angiogenesis, ECM remodeling, and the inflammatory response in CAC. They also affect the immune system by modulating differentiation and immune activity of immune cells, recruitment of macrophages, and recruitment of neutrophils. Herein we describe the immunomodulatory role of MMPs in CAC to facilitate treatment of this special type of colon cancer, which is preceded by detectable inflammatory bowel disease in clinical populations.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Classification and structural characteristics of matrix metalloproteinases

MMPs are a kind of calcium-and zinc-dependent proteolytic enzyme, that exist in invertebrates, vertebrates and plants. They are produced by multiple cells and tissues, with neutrophils and dermal fibroblasts being the main sources. Connective tissue, pro-inflammatory and uteroplacental cells, including endothelial cells, osteoblasts, cytotrophoblasts, lymphocytes, macrophages, and vascular smooth muscle are also capable of secreting MMPs. Degrading the ECM is the main function of MMPs. The ECM plays an important role in the proliferation, growth, organization, differentiation, migration of cells, and in the exchange among information cells; it also acts as a physical barrier for microorganisms. To date, 28 types of MMPs have been found. The homologous domains of these MMPs include the signal peptide domain, propeptide domain, catalytic domain and hinge region or linker peptide along with a hemopexin domain. The hinge region connects the catalytic domain to the hemopexin domain. MMPs are divided into collagenases (e.g., MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (e.g., MMP-2 and MMP-9), stromelysins (e.g. MMP-3, MMP-10, and MMP-11), matrilysins (e.g. MMP-7 and MMP-26), membrane-type MMPs (MT-MMPs) (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25), and others (MMP-12, MMP-19, MMP-21, and MMP-28) based on structural features and substrates. In particular, gelatinases have a special additional exosome insert in the catalytic domain called the collagen binding domain; matrilysins lack a C-terminal hemopexin-like domain linked by a hinge or linker region, and MT-MMPs have a C-terminal transmembrane domain with a short cytoplasmic tail. The classifications and structures of MMPs are shown in Figure 1.

Regulation of MMPs at multiple levels

MMP activity is regulated in three different ways, through transcriptional regulation, inhibition by specific inhibitors, or activation by the proenzyme. At the transcriptional level, the activator protein (AP) -1 and -2 sites, the NF-κB site, the signal transducer and activator of transcription site, the polyomavirus enhancer-A binding protein-3 site, and others are key transcription binding sites for regulation of the MMP gene. The AP-1 site is located close to the most proximal promoter of the typical TATA box and is the major mediator in MMP gene regulation. In many MMP promoters that contain AP-1 site, the juxtaposed transcription factor binding sites bind multiple erythroblastosis twenty-six factors, which determine the peculiarities among different genes and affect gene expression. The polyomavirus enhancer-A binding protein-3 site, can combine with members of the erythroblastosis twenty-six factors family of oncoproteins and work in synergy with the AP-1 site nearby to promote the production of MMPs among cancer cells for migration and invasiveness. MicroRNA is a non-coding single-stranded RNA. In liver cancer cells, mRNA expression of MMP-2 and MMP-9 is up-regulated as a result of the inhibition of miR-21, which stimulates the invasion and migration of tumor cells. miR-224 is associated with gene expression of MMP-1, which enables breast tumors to metastasize to the bone. NEMO-binding domain, a synthetic peptide corresponding to the S100A4-binding domain of methionine aminopeptidase 2 [MetAP2], blocks interaction between the metastasis−enhancing calcium−binding protein (S100A4) and its effector protein (MetAP2). And this blockage inhibits specificity protein 1 (Sp1) and ultimately leads to the downregulation of MMP-14 gene expression. MMP-7 antisense oligonucleotides inhibit gene expression of MMP-7 and inhibit the metastasis of gastric and colon cancer by interfering with protein translation or promoting mRNA degradation. The modulation of gene expression differs in various physiological and pathophysiological events, such as Ets1 enhancing gene expression of MMP-1 through c-Jun. Note that modulation of the MMP gene can be affected by several stimuli. Some factors, such as phorbol esters and ultraviolet B radiation, activate expression of the MMP gene, whereas others, such as transforming growth factor β (TGF-β), glucocorticoids and retinoic acid, suppress it. In addition, the MMP gene may be induced indirectly by several signaling pathways. Inflammatory cytokines, for example, interleukin (IL)-1 and tumor necrosis factor, indirectly influence MMP gene expression and activate the ceramide signaling pathway. Three distinct MAP kinase pathways, p38, ERK1/2 and c-Jun N-terminal kinase (JNK) affect ceramide-dependent MMP-1 gene expression in human skin fibroblasts. MMPs genes are not generally upregulated by gene amplification or mutation like classical oncogenes. Usually transcriptional changes and/or epigenetic modifications result in an upregulation of MMP gene expression in colorectal cancer (CRC). Besides transcriptional regulation, MMP activity is related to proMMPs, which are secreted as inactive zymogens. Extracellular activation of proMMPs involves two steps. First, the N-terminal sequence of the propeptide domain is cleaved and releases the Zn2+-binding site stemming from catalytic domain exposition. Second, propeptide cleavage resulting in an active form of enzyme. For example, proMMP-9 was activated and then generated MMP-9, thus catalyzing angiogenesis via the FGF-2/FGFR-2 pathway. In addition, the activity of MMPs is regulated by α2-macroglobulin and tissue inhibitors of MMPs (TIMs), the two main endogenous inhibitors. Thiol-modifying reagents, sodium dodecyl sulfate, and oxygen radicals also induce activation of MMPs in vitro.Variation in temperature or a decrease pH in the physicochemical environment serves the same purpose.

Immunological function of MMPs

The immune system, human beings’ main defense against disease, is indispensable. It eliminates foreign invaders through the immune response in a sophisticated and scientific way. Components that participate in immune regulation include innate immune cells, which act as early-responders, and adaptive immune cells, which enhance the response and generate immunological memory and molecules. Cytokines and chemokines control the immunoreaction in time and space. They take part in cell migration to the site of inflammation, proliferation, intercellular communication, and cell death. The immune response does not necessarily lead to an inflammatory response, but inflammation accompanies the immune response in most cases. Inflammation commonly occurs after infection and damage. When antigens enter the body, macrophages or epithelial cells secrete chemokines, causing an increase in the vascular epithelial cell gap and vascular expansion; a large number of neutrophils, mast cells, basophils, and eosinophils infiltrate from the blood vessels into tissue fluid, resulting in localized febrile response, redness, swelling, and pain the cardinal signs of inflammation. An excessive immune response can lead to inflammation, such as pathogenic microbial infection, tumor, autoimmune disease, and tissue damage induced by physical or chemical elements. Immune cells and cytokines play an important role in the occurrence and resolution of inflammation. Numerous immune cells (e.g., macrophages, neutrophils) infiltrate the inflamed area and activated immune cells to release inflammatory factors (e.g., TNF-α, IL-6 and IL-1β), which worsens the inflammation. Resolving this inflammatory response requires the release of anti-inflammatory cytokines (e.g., IL-10) by immune cells.

The composition of the tumor microenvironment is very complex. The tumor stroma is composed of the ECM, immune cells, fibroblasts, endothelial cells and other non‐neoplastic cells. MMPs produced in immune cells take part in innate and acquired immunity. Many immune cells express low levels of MMPs in the resting state. In mouse splenic CD4+ T cells, membrane-anchored disintegrin metalloproteinase-10 (ADAM-10) and ADAM-17 mRNAs are expressed highly, whereas the mRNA expressions of MMPs, such as MMP-2, MMP-9 and MMP-14 are low. Under normal conditions, when the expression of inflammatory cytokines and chemokines increases, MMPs of immune cells are secreted and activated. When stimulated by IL-8, TNF, or chemo-attractive formyl-Met-Leu-Phe peptide, MMP-9 in neutrophils is immediately released from gelatinase granules (also called tertiary granules). In addition, TIMP1 protein is not expressed in neutrophils. However, B cells, T cells, and unstimulated human peripheral blood monocytes are able to express TIMPs in the steady state. The transcript levels of TIMP1, TIMP2 and TIMP4 are expressed more highly in monocytes than in B cells or T cells. In contrast, TIMP3 mRNA is highly expressed in B cells. ADAM17 and MMP-8 cleave the lymphotoxin (LT)-α1β2 heterotrimer, causing the release of heterotrimers from polarized T helper 1 (TH1) and TH17 cells. The combination of LTα1β2 heterotrimers and LTβ receptor activates primary synovial fibroblasts, eventually leading to synovial inflammation. The OX40 (a member of the TNF superfamily)–OX40 ligand axis is involved in numerous inflammatory diseases, anti-tumor immune responses and metabolic syndromes. MMP-2-specific CD4(+) T cells exist in tumor-infiltrating lymphocytes from melanoma patients, and they have an inflammatory T(H)2 (Type 2 helper T cells) profile. Dendritic cells (DCs) with MMP-2 initiates TH2 responses against several melanoma-associated antigens. As a reaction to exogenous melanoma antigens, active MMP-2 promotes TH2 cell differentiation, degrades the IF-α/β receptor in immature DCs and increases the protein expression of OX40 ligand in mature DCs. Therefore, researchers speculate that the mechanisms by which activated MMP-2 promotes tumor development is as follows: MMP-2 polarizes tumor-infiltrating lymphocytes toward a TH2 cell phenotype, which restrains the tumoricidal TH1-type response. Moreover, MMP-2 inhibits the powerful promoter of TH1 cell polarization-IL-12 subunit p35 (IL-12α).

Important factors in building an immune response are efficient migration of neutrophils along a chemotactic gradient and extravasation through blood vessels and tissues to sites of infection. MMPs play a role in these processes by modifying chemotactic agents. A cleavage mediated by MMP-7 releases the heparan sulfate proteoglycan syndecan 1, and its associated CXC-chemokine ligand 3 (CXCL3), which attracts neutrophils to the site of infection. MMP‐8 which is mainly produced by neutrophils can be detected in the inflammatory response and some malignant tumors. In one study, there was a persistent inflammatory response after MMP-8-deficient mice were injected with methylcholanthrene. The incidence of skin tumors in male mice of this type increased significantly; female mice that were treated with tamoxifen or had their ovaries removed were more likely than wild-type mice to develop tumors. These results indicate that MMP-8 has a tumor suppressor function to some extent. This function is also supported by the finding that MMP-8 inhibits melanoma growth in vitro and in vivo. MMP-8 is necessary for recruiting chemokine CXCL6 to activate neutrophils; neutrophils are not able to migrate to sites of LPS administration without MMP-8. IL-8 is a prototype chemokine that activates neutrophils. There is positive feedback between MMP-9 and IL-8. Stimulated by IL-8, neutrophils secrete gelatinase granules whose main component is MMP-9. MMP-9 truncates an amino-terminal fragment of IL-8 for large increases in IL-8 potency. MMP‐2 cooperates with MMP‐9 to promote neutrophil infiltration. MMP-2 and MMP-9 have synergistic effects on cleaving CXCL5 to increase neutrophil migration to the peritoneum during IL-1β-induced peritonitis. Meprins are members of the metzincin superfamily of zinc metalloproteinases, the cleaved substrate involved in many pathological processes, such as inflammation, cancer and fibrosis. Meprins participate in activating MMP-9 in the immune response. MMP-3 is an efficient activator of proMMP-9. The cleavage mediated by meprins improves the activation kinetics of proMMP-9 by MMP-3. In contrast, MMP-2 may suppress the inflammatory response inactivating monocyte chemotactic protein 3 or Chemokine (C-C motif) ligand 7.

Monocyte precursors are capable of differentiating into local macrophages in tissues. In different microenvironments, the cell surface phenotypes and functions of macrophage populations are heterogeneous. Macrophages play a prominent role in anti-infection and, anti-tumor activity and immune regulation. Similar to what happens in neutrophils, macrophages move directionally along the concentration gradient of certain chemicals and accumulate at the site of the lesion, where these substances are released. Metalloproteinases are able to affect macrophage recruitment. In mice with TIMP3-null mammary glands, the inflammatory response is exacerbated, the number of CD3+ T-cells increases, and macrophage infiltration is more pronounced than in wild-type mice glands. A classic means of activating macrophages (classically activated macrophages or M1 macrophages) is through Toll-like receptor ligands and pro-inflammatory mediators, such as TNF-α, interferon-γ (IFN-γ), and IL-1. Additionally, alternatively-activated macrophages, or M2 macrophages, can also be alternatively activated by distinct mediators, like IL-4 and IL-13. In inflammation, M1 macrophages effectively dispose of infectious organisms, and orchestrate angiogenesis and the ingress of connective tissue cells to form a granuloma. The function of MMPs ECM remodeling is vital in that process. In healing, M2 macrophages may promote connective tissue cells to remodel the ECM. In vitro-differentiated M1 macrophages, mRNA expression of MMP-1, MMP-3, MMP-7, MMP-10, MMP-14 and MMP-25 are increased, and mRNA expression of TIMP-3 is decreased. mRNA expression of MMP-11, MMP-12, MMP-25 and TIMP-3 are upregulated, whereas MMP-2, MMP-8 and MMP -19 were reduced in M2 macrophages. Researchers speculate that the function of macrophages is related to the profile of MMP expression profile. The upregulation of MMP-12 in M2 macrophages is a major influence on the formation of aneurysms. Higher levels of MMP-1 collagenase may might be linked to higher collagenolytic activity of M1 macrophages. Macrophages also participate in specific immune response by releasing either pro- or anti-inflammatory cytokines. MMP-14 (MT1-MMP) can control inflammatory gene responses. MMP-14-deficient macrophages produce excessive chemokine and cytokine responses to immune stimulation both in vitro and in vivo: they increase the gene and protein expression levels of the pro-inflammatory IL-12p40 (also called IL-12β) and IL-6, along with decrease the gene and protein levels of the anti-inflammatory IL-10. Phosphoinositide 3-kinase δ (PI3Kδ), a key regulator of macrophage immune responses, is the downstream transcriptional target of MMP-14. Protein expression of MMP-14-dependent PI3Kδ evokes the expression and activation of a PI3Kδ/Akt/GSK3β signaling axis, thus mediating the immunoregulatory Mi-2/nucleosome remodeling and nucleosome remodeling and deacetylase to limit the expression of proinflammatory mediators in macrophage. MMP-12 originating from macrophages participated in abrogating the acute immune response. In MMP-12-deficient mice, leukocytes accumulated at the site of infection. MMP-12 cleaves and inactivates numerous CXC-chemokines and CC-chemokines which are implicated in the influx of leukocytes at the site of inflammation.

MMP-7 is involved in the immune activity of macrophages and neutrophils. One immunological function of MMP-7 is proteolytically activating α-defensins (cryptdins), which are a group of six cationic anti-bacterial peptides that work by disrupting bacterial membranes. When stimulated by bacterial products, such as LPS and lipoteichoic acid, α-defensins are secreted from neutrophils, monocyte/macrophages and Paneth cells at the base of the crypts in the small intestine. α-defensins also act as the chemo-attractants for monocytes, T-cells and DCs to connect innate immunity to adaptive immunity. α-defensins are also mitogenic for epithelial cells and fibroblasts to aid in wound healing.

The cDNA sequence of MMP-25 from Japanese sea bass (Lateolabrax japonicus) (LjMMP25) regulates the production of inflammatory cytokines and promotes phagocytosis and bactericidal activity in monocytes/macrophages. Moreover, LjMMP25 regulates the inflammatory response by modulating NF-κB activity during innate immunity. Macrophages have a negative impact on cancer treatment. They create an inflammatory environment to promote tumorigenesis and tumor progression, such as angiogenesis, migration and invasion, and immunosuppression. For example, the penetration of cancer cells and leukocytes into the cerebral vessels is a complex multi-step process. The activity of macrophage-derived MMP-2 and MMP-9 is pivotal to leukocyte’s ability to penetrate the parenchymal basement membrane in mice with the ability autoimmune encephalomyelitis. These MMPs can be inhibited to protect the brain parenchyma from damage by preventing the infiltration of leukocytes. Moreover, the activation of TNF‐α by MMPs contributes to tumor progression. The membrane-bound precursor, proTNF‐α, is mainly expressed in macrophages. ADAM17 (a TNF-converting enzyme) and MMPs, such as MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-14, MMP-15 and MMP-17, convert proTNF-α into TNF‐α.

Multifaceted role of MMPs in biological and pathological processes

Under normal physiological conditions, the activities of MMPs are controlled by various stimuli at multiple levels. However, under pathological conditions, this dynamic balance is broken. Over-degradation of the ECM due to overactivation of MMPs, is associated with a great many diseases, such as cardiovascular disease, arthritis, periodontal diseases, osteogenesis imperfecta, disorder of the central nervous system, tumor invasion and metastasis, age-related macular degeneration and many other pathological states. Moreover, a decrease in MMPs can give rise to hypertensive pregnancy, preeclampsia, and inflammatory damage.

As mentioned above, there are several main types of MMPs including collagenases, gelatinases, stromelysins, matrilysins, and MT-MMPs. Different MMPs have different three-dimensional structures, along with corresponding specific inhibitors or drugs. A typical MMPs consists of a prodomain, a propeptide, a catalytic domain and a hemophosphate domain. Approximately 80 amino acids make up the propeptide domain, and about 170 amino acids make up the catalytic metalloproteinase domain. The polypeptide folding of the MMP catalytic domain is basically superposition. The domain consists of a five-stranded β fold sheet, three α helices, and connecting rings. It contains two zinc ions and up to three stable calcium ions. The joint peptide contained in MMPs consists of a hinge region of variable length and a hemophosphate domain of about 200 amino acids. Exceptions include MMP-7, MMP-26, and MMP-23, which lack the hinge region and heme domain; MMP-23 has unique cysteine-rich domains and immunoglobulin domains. MMP-1, MMP-8, MMP-13, and MMP-18 are collagenases, and their key feature is their ability to cleave interstitial collagen I, II, and III at specific sites three-fourths away from the N-terminus. MMP-2 and MMP-9 are gelatin enzymes, which have three type II fiber-fiber-domain repeats in the catalytic domain and can bind to gelatin, collagen and laminin to digest denatured collagen. MMP-3 and MMP-10 are matrix lysins that digest ECM components. The classification of common MMPs implied in pathological processes is shown in Table 1. Collagenases recognize the substrate via a hemopexin-like domain, degrade fibrillar collagen and affect the ECM environment. Collagenases are closely related to the occurrence and development of diseases characterized by the degradation or change in the ECM are closely related to collagenase, including heart failure, atherosclerosis, cancer, arthritis, abdominal aortic aneurysm. In addition, they play a protective role in some diseases, for instance hypertrophic cardiomyopathy. Furthermore, collagenases improve liver fibrosis. MMP-1 inhibits the development of atherosclerosis. MMP-8 plays a protective role in arthritis. Another category of MMPs is gelatinase. These MMPs act as digestive agents for components of the ECM, such as type I and IV collagen. They are induced or inhibited by a diverse range of resolvable factors, including growth factors, cytokines and hormones, and are acted on by cellular contacts through specific signaling pathways. MMP-9 has pro-inflammatory properties, whereas MMP-2 has pro-homeostatic properties. Gelatinases have a profound influence in inflammatory process and tumor progression and have therefore long been considered one of the most significant anti-tumor targets. In terms of non-neoplasticity, gelatinases are mainly involved in cardiovascular pathology and auto-immune diseases. Moreover, MMP-9 is associated with many respiratory diseases. A reduction in vascular MMP-2 and MMP-9 gives rise to hypertensive pregnancy and preeclampsia. Stromelysins, another class of MMPs, have a structural domain arranged similarly to that of collagenases. However, these MMPs do not cleave fibrillar collagen type I. An important physiological function of stromelysins is to activate other members of the MMP family. The most widely described pathological role of stromelysins is in cancer progression. In addition, they function in the progression of cardiovascular, degenerative, and auto-immune diseases. Matrilysins, yet another category of MMPs, do not contain a hemopexin-like domain and are able to decompose collagen type IV but not type I. Matrilysins are associated with a number of pathological conditions in humans, mainly cancer and, respiratory, cardiovascular, and neurological diseases. A large number of studies have demonstrated that MMP-7 acts in the development and migration of cancer. Moreover, MMP-7 also has a critical role in pathogenesis of tonsillitis and permanent hearing loss. A study confirmed the early role of MMP-26 in the invasion and angiogenesis of malignant tumors. The final member of the MMPs family discussed here is MT-MMPs, which are an important mediator of infiltration. The influence of MT-MMPs on pathological process is mainly reflected in their promotion of tumor invasion. The ability to activate MMP-2 is one of the reasons why most MT-MMPs play these roles. A different example is MMP-17, which has no regulatory effect on MMP-2 although it still affects tumor invasion. In addition, studies have demonstrated that MT-MMPs are also implicated in the pathological process of osteoarthritis, atherosclerosis and Alzheimer’s disease. MMPs are medicinal targets highly relevant to the treatment of a variety of diseases. As understanding of the role of MMPs in biology and pathology increases, greater understanding of the structural similarities and differences among MMP families makes it possible to discover highly selective MMP inhibitors.

In the tumor microenvironment, the activity of a variety of MMPs, including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-14, are up-regulated. These MMPs participate in tumor proliferation, survival, and angiogenesis, enabling replication immortality, invasion/migration, immunity evasion and other processes. These MMPs control tumor cell growth by the releasing of ectodomains of growth factor, regulating the bioavailability of growth factors and regulating signaling pathways related to cell proliferation. MMP-3 and MMP-7 expression in tumor cells may contribute to an apoptosis resistant phenotype. In addition, the MMP family is necessary for tumor angiogenesis via a two-way action, that is promoting or inhibiting angiogenesis. MMP-1, MMP-2, MMP-7, MMP-9 and MMP-14 regulate this process, and the first three of them play critical roles. Another key process in which MMPs are the migration of tumor cells. MMP-14 is among the key contributors to cancer invasion and promotes cancer development by activating proMMP-2 and degrading the ECM to promote cancer migration. MMP-7 acts in tumor cell metastasis by activating the ERK 1/2 and JNK 1/2 signaling pathways. MMP-1, MMP-2, MMP-8, MMP-11, and MMP-13 are implicated in the regulation of tumor cell migration. Finally, MMPs, such as MMP-14, also participate in tumor immune monitoring. Increasing attention has been paid to the role of MMPs in tumor immune regulation, such as their effects on inflammatory and immune responses, the tumor immune microenvironment and their diagnostic or prognostic potential.

Relationship between MMPs and immune-related diseases

MMPs affect the process of colitis. MMP-2 is causative for inflammatory bowel disease (IBD), which is derived from weak mRNA expression of pro-inflammatory cytokines including IFN-γ and TNF-α, and weak protein expression of IL-6 and less overgrowth of the colonic lumen by potentially pro-inflammatory enterobacteria from the commensal gut microbiota. MMP-9 plays a potentially key role in the progress of ulcerative colitis (UC) by regulating the immune system. MMP-19 coordinates the appropriate innate immune response in colitis, which is critical to balancing the host response to colon pathogens. MMP-9 is a member of MMPs closely related to cancer. MMP-9 is related to immune infiltration in pan-cancer and can be used as a biomarker of cancer prognosis and metastasis. It is overexpressed in peripheral blood NK cells of prostate cancer. And MMP-9 also effectively reduces the tumor killing-effect of T cells via cutting the MHC class I molecule, cell surface antigen-presenting complex molecules expressed in melanoma cells. In addition, high expression of MMP-11 is associated with worse survival rate in breast cancer, which is related to a low immune response, such as the reduction in the number of CD8+T cells, CD4+T cells, B cells and activated DCs.

Relationship between MMPs and inflammatory diseases

Inflammation is a fundamental pathological process that occurs when biological tissue is stimulated by certain kinds of injury, such as trauma and infection. Topical presentations of inflammation include redness, swelling, heat, pain and functional impairment. Systemic reactions include fever and changes in peripheral blood levels. MMPs are vital elements implicated in the manifold regulation of inflammation. In one study, levels of some MMPs, such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13, were significantly elevated in ulcer biopsies from patients with inflammatory disease. MMPs have not only a negative influence, but they also have an impact on vascular permeability, ECM remodeling, epithelial proliferation, and angiogenesis in different stages of inflammation. In a model of colonic injury induced by sodium dextran sulfate, MMP-10 had a positive effect on disease. Because the progression of damage due to lack of MMP-10 is accelerated with viciousness-potential, enhancing expression of MMP-10 is helpful. A similar observation can be found for MMP-19.

Important role of MMPs in colitis

Chronic inflammatory disease is often associated with the occurrence and development of various cancers. A classic example is the increased risk for CAC in patients with IBD. In chronic environments marked by chronic inflammation, the ECM is a major factor in maintaining and promoting tumor growth, and MMPs are the major protease involved in the pathogenesis of IBD. Although both sporadic CRC and CAC are malignancies of the colon, CAC differs from sporadic colon cancer in several respects. CRC is produced through three main pathways: the adenomato-carcinoma sequence, the serrated pathway, and the inflammatory pathway. In contrast, the development of CAC is associated with the inflammatory-dysplasia-carcinoma pathway. MMPs counteract ECM proteins expressed in the gastrointestinal tract during inflammation. Therefore, this study was conducted to evaluate the role of MMPs in CAC and its related mechanisms. The essential role of these enzymes in the remodeling and destruction of tissue in IBD has been well documented. Pathological results of IBD, progressive mucosal disintegration (e.g., ulcers and fistulas) and fibrosis due to excessive deposition of collagen (the main component of ECM), is related to a disruption in the balance between composition and breakdown of the ECM. As an important molecule in mucosa and submucosa, ECM is the substrate of MMPs, which is why MMPs play such an essential role in the development of IBD. In Crohn’s disease (CD), TNF-α and activated T cells stimulate mesenchymal cells to increase the secretion of MMPs, and then MMPs causes tissue damage by degrading the lamina propria matrix. MMP-3 and MMP-9 participate in the formation of fistula in CD by degrading the ECM. Moreover, MMPs are the key element in wound healing in the late stage of IBD through their effects on degradation of the ECM. MMP-1, MMP-7, and MMP-10 are expressed in migratory enterocytes in this process, which is important for epithelial regeneration and wound granulation. Furthermore, MMP-3 is crucial in scar contraction and ECM remodeling.

Regarding the ECM, MMPs have roles in a diverse array of substrates, including cytokines, chemokines, TNF-α, α1-antitrypsin/α1-antichymotrypsin, IL-1β, stromal cell-derived factor-1, growth factors and so forth. Some factors, such as TNF-α and IL-1β, in turn, stimulate the production of MMPs. Injury to the intestinal barrier is also responsible for IBD. When the intestinal barrier is disrupted, gene and protein expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10 and MMP-13 increase, and leukocytes are summoned to inflamed areas. MMP-8 and MMP-9 are released from neutrophils to regulate proinflammatory cytokines and chemokines to increase the number of leukocytes and eliminate bacteria. Macrophages phagocytose bacteria, along with MMP-9 released externally and MMP-12 entering into the phagosome. MMP-12 has a direct bactericidal effect. Briefly, when bacterial pathogens invade, MMP-12 is mobilized to macrophage phagolysosomes and adhere to bacterial cell walls, destroying cell membranes and causing bacterial death. MMP-7 plays an indirect bactericidal role by activating and releasing bactericidal alpha defensins into the gut lumen. MMP-10 from infiltrating myeloid cells participates in the recovery of DSS-induced damage to the colon. Research has also shown that the susceptibility to colitis, including significant disease progression, increased mortality, severe tissue destruction, increases level of pro-inflammatory regulators in the colon and plasma, and a significant delay in neutrophil infiltration and persistent inflammation, increased markedly in MMP-19-null mice. In IBD, MMP-14 in endothelial cells promotes angiogenesis, which is achieved by combining the C-terminal fragment of MMP-14 substrate thrombospondin-1 with CD47/αvβ3 integrin to produce nitric oxide. Moreover, the migration of macrophages that lack MMP-19 is reduced in vivo and in vitro and the mucosal barrier is damaged. Chemokine fractalkine (CX3CL1), a substrate of MMP-19, is an essential component of the response to DSS in acute colitis. Because CX3CL1 receptors exist on innate immune cells (e.g., macrophages, neutrophils), impaired immune cell trafficking may be associated with a lack of the soluble CX3CL1 in MMP-19-deficient mice. Mice without the receptor CX3CR1 have more serious symptoms of DSS-induced colitis. The application value of MMPs as biomarkers in IBD has also been recognized. A number of studies have demonstrated the high sensitivity of MMP-9 in evaluation of active UC. In addition, through an analysis of emerging BiomARKers (EMBARK), the researcher not only proposed that the combination of fecal calprotectin and serum MMP-9 can be used as a biomarker of UC, but also confirmed the value of MMP-9 as a biomarker of CD, indicating the combination of fecal calprotectin, serum MMP-9 and serum IL-22 can be used as a biomarker of CD.

In conclusion, MMPs participate in the host immune defense, would healing, and epithelial regeneration and they have bidirectional effects in IBD. On the one hand, they are involved in the development of IBD through the process of inflammation. MMPs are indirectly associated with progressive organ damage, ulceration or over accumulation of collagen, the persistence of inflammation, and fibrosis because of their substrate ECM. On the other hand, some members of MMP family have an inhibitory effect on inflammation.

Key MMPs in CAC

CAC is a very common fatal complication of IBD. The pathogenesis of CAC is multifactorial, although a key driver of colitis is neoplastic progression. The lifetime risk for CAC in IBD patients is 15-40%, and CAC accounts for about 15% of mortality in these patients. Chronic inflammation generates oxidative stress that induces DNA damage that might activate some oncogenes and inactivate some anti-oncogenes. Related mechanisms include oxidative base lesions, replication stress, DNA crosslinking, and strand breaks, which eventually lead to genomic destabilization and tumorigenesis. MMPs play a roles in both promoting and inhibiting regulation of CAC development and progression, as shown in Table 2. The main role of MMPs in colitis and CAC is shown in Figure 2, and the network of MMPs that interfere with CAC is shown in Figure 3. A list of all genes mentioned here could be found in Table S1.

MMPs degrade the protein components of the ECM and basement membranes, which provides a channel for cancer cells to invade to the vascular and lymphatic systems as well as promotes metastasis. In the process of tumor growth, MMPs are up-regulated, which strengthens the permeability of vascular endothelial cells, thereby increasing cell proliferation, migration and angiogenesis. Histone demethylase (JMJD2D) and β-catenin interacts physically (JMJD2D demethylates H3K9me3 on the promoter of β-catenin target genes), which increases the promoter activity of target genes (including MMP-2 and MMP-9) of β-catenin; activates transcription of MMP-2, MMP-9, and others; and ultimately cause CRC cells to proliferate, migrate and invade, and form colorectal tumors in mice. In a mouse model of tumor invasion, macrophages infiltrate and express MT1-MMP, resulting in activation of MMP-2 and consequent inhibition of TGF-β. This process leads to submucosal invasion of epithelial cells when it occurs in conjunction with KRAS or phosphatase and tensin homolog deleted on chromosome 10. Specifically, when the inhibition of TGF-β is accompanied by the expression of KRAS, activation of the epidermal growth factor receptor (EGFR) signaling pathway is increased as a result of increased protein expression of epiregulin and mRNA expression of Errb1. When the inhibition of TGF-β is accompanied by phosphatase and tensin homolog deleted on chromosome 10 deletion, mRNA expressions of cyclin-dependent kinase (CDK) inhibitors (Cdkn2b/p15Ink4b, Cdkn1a/p21Cip1 and Cdkn1b/p27Kip1) is down-regulated. The level of MMP-3 secreted from myofibroblasts is up-regulated in IBD and tumorigenesis. TNF-α and bradykinin enhance expression of MMP-3 at a transcriptional level through the protein kinase C/protein kinase D1/mitogen-activated protein signaling pathway, and thus mediate CAC. This mediating effect is related to the promotion of tumor invasion by MMP-3. MMP-7 is connected to the occurrence and progression of CAC, and is expressed intensely at crypt bases of epithelial cells and in dysplastic CAC biopsy, as observed in CRC. Because of the lack of adenomatosis polyposis coli, the WNT signaling pathway is deregulated and β-catenin and T-cell factor-4 accumulate. Hence, the expression of MMP-7 up-regulated. In addition, fibroblast growth factor receptors in cancer-related fibroblasts activate Stat-3 signaling, thereby inducing MMP-7 expression. In contrast, the highly expressed MMP-9 in CAC inhibits the tumor by affecting the Notch signaling pathway. Specifically, MMP-9 activates p21WAF1/Cip1 by regulating notch activity, a key transcription factor in epithelial cell lineage, resulting in β-catenin inhibition and cell cycle arrest. MMP-9 from the colonic epithelium also acts as a tumor suppressor by activating the MMP-9-Notch1-ARF-p53 axis, which leads to apoptosis and DNA damage. Previous study claimed that epithelium-derived MMP-9 is beneficial for chronic inflammation, regardless of tissue origin, in contrast to neutrophil-derived MMP-9. They also proposed that MMP-9 (stemming from epithelium or neutrophils) is a pivotal regulator of acute IBD and sporadic cancers. MMP-9 reduces reactive oxygen species and DNA destruction in CAC as well. Some researchers have also found that the hemopexin domain of MMP-9 has an inhibitory effect on the metastasis and adhesion of CRC. The decrease in MMP-9 in plasma causes down-regulation of angiostatin synthesis, which results in tumor growth and vascularization. MMP-9 expressed in the colonic epithelium maintains the microbiota balance. Antimicrobial peptides including REG3 and S100A families, are effective agents of the innate immune system. In transgenic mice constitutively expressing MMP-9 in the colonic epithelium mRNA levels of TNF-α, IL-6, IL-1β and IFN-γ increased, but mRNA levels of IL-22, REG3γ and S100A8 decreased. MMP-9 maintains epithelial and mucosal integrity by increasing mucin and intestinal trefoil factor protein levels and down-regulating the STAT3 pathway in vivo. Moreover, MMP-9 acts on the EGFR-nuclear transcription factor-Sp1 signaling pathway to sustain epithelial mucosa and functioning as well as immune homeostasis.

MMP-9 and MMP-10 are only significantly expressed in inflamed tissue, not normal colon tissue, and they start to peter out when healing begins. MMP-10 is mostly expressed by macrophages. In UC, it is found in enterocytes at the margins of ulcers and in the cells of granulation tissue. Researchers believe that MMP-10 from infiltrating bone marrow cells plays a role in resolving the inflammation. With a lack of MMP-10, susceptibility to DSS-induced colitis increases, and prolonged IBD may eventually lead to dysplasia. In miR-148/152-deficient mice, expressions of MMP-10 and MMP-13 increases, thus activating pro-TNF-α turning into TNF-α and promotes activation of the NF-κB signaling pathway. Damaged functioning of the intestinal barrier accelerates colitis and CAC. Similarly, MMP-11 is virtually absent in regular tissues. The mRNA level of MMP-11 is related to CAC in some way. The mRNA level of MMP-11 is up-regulated in CAC, and is associated with the increase in the number of β-catenin accumulated crypts. The proton pump inhibitor-omerprazole and TNF-α blocker-infliximab reduce the mRNA level of MMP-11 and induces cells apoptosis in CAC. MMP-13 is highly increased in CAC colonic tissues, but do not change as the CAC progression. Compared to other MMPs, MMP-14 (MT1-MMP) does not increase markedly in CAC. Researchers have also found that Omerprazole and Infliximab were able to down-regulate the mRNA levels of MMP-14. In a mouse model of CAC, miR-128, miR-134 and miR-330 are influenced by Dicer1. These microRNAs inhibit tumor growth in vitro and in vivo and modulate expression of MMP-3, MMP-10, and MMP-13.

Mechanisms underlying of typical MMPs in CAC

In CAC, typical MMPs affecting the organism’s immune function and their expressions are regulated by the immune system, as shown in Figure 4. MMP-7 decreases the sensitivity of mice to intestinal bacteria. Specifically, MMP-7 knockout mice do not activate pro-a-defensins in the gut to their mature active forms, with the result that these mice are highly susceptible to intestinal bacterial infection. MMP-8 affects the immune response to tumor and helps to resolve necrosis, which is positively related to the degree of primary tumor necrosis and blood neutrophil count, as well as negatively correlated with destructive inflammatory infiltration and Crohn’s-like lymphoid reaction. MMP-8, which is involved in resolving acute and chronic inflammation and helps to recruit neutrophils during acute inflammation, is mainly produced by neutrophils. It plays a role in the recruitment of neutrophils to necrotic areas and in tissue remodeling, including collagen breakdown. MMP-9 is associated with the onset of lymphadenitis in patients with CAC, and is significantly up-regulated before the onset of lymphadenitis in these patients. In addition, MMP-9 maintains the integrity of epithelial mucosa and acts as a tumor suppressor in CAC, which is inseparable from its function of mediating the level of proinflammatory cytokines. The linings of gastrointestinal epithelial mucosa act as an external physical barrier and a functional immune barrier for an immune monitoring system. The imbalance in immune cells is crucial to the development of cancer. The inflammatory cytokines released by immune cells function in immune defense, and promote the development of cancer in specific circumstances. MMP-9 increases mRNA levels of IL-6, IL-1β, TNF-α and IFN-γ, but decreases the mRNA level of IL-22. Regarding the regulation of MMPs by the immune system, elevated MMP-8 is associated with systemic inflammation and increased secretion of various cytokines, including IL-1ra, IL-7 and IL-8, and is negatively associated with the number of tumors infiltrating mast cells. In a mouse model of colitis-associated CRC, the NF-κB mediated inflammatory reaction promotes protein expression of cyclin D1, phosphorylated ribosomal protein S6 and MMP-9 in the colon tissues of these mice, which plays a beneficial role in CRC progression. In the mouse model of CAC, MMP-9 expression is associated with excessive angiogenesis and cell proliferation, which is related to CXCL2 and neutrophil recruitment. CXCR2 is present in neutrophils and interacts with CXCL2. This interaction promotes the recruitment of neutrophil and the synthesis of MMP-8 and MMP-9. The proinflammatory factors IL-17 and IL-21 increase the MMPs secreted by human intestinal fibroblasts, including MMP-1, MMP-2, MMP-3 and MMP-9. Among them, the inducing effect of IL-17 on MMP-1 and MMP-3 depends on the rapid activation of mitogen-activated protein kinase. The regulation of MMPs by IL-21 does not occur at the level of transcription and translation and stimulating fibroblast with IL-21 does not increase the intracellular level of MMP RNA transcripts and proteins. The up-regulation of MMPs by IL-21 may depend on preferentially increasing the secretion of preconstituted or newly synthesized MMPs. In addition, expression of MMPs is regulated by TNF-α and IFN-γ.

Potential clinical applications of MMP inhibitors

Clinical trials of MMPs mainly focus on three factors. They are respectively the changes in clinical levels of MMPs in different disease states, the clinical use of MMP inhibitors in colitis and colorectal cancer, and combining MMPs and some regulatory factors with other drugs to control inflammation and tumors. MMP-2, MMP-3, MMP-7 and MMP-9 are the key MMPS in this process. However, current clinical trials have shown that inhibiting MMPs has no obvious effect on tumor responses, although it has a certain role in stabilizing the condition of diseases.

Many MMPs are upregulated in IBD. These MMPs remodel tissue and release several small protein fragments. In a clinical trial with 164 volunteers, these protein fragments could be used to distinguish between CD and UC. For example, measuring segments of vimentin (MMP-2 and MMP-8 decomposed and citrullinated-vimentin [VICM]) and type III (MMP-9 decomposed collagen type III [C3M]) can distinguish between CD and UC. A total of 138 participants took part in an IBD-related study, including different types of disease. Fecal MMP-9 can be used to diagnose and differentiate between UC and pouchitis, because it is strongly associated with clinical, histological, and endoscopic activities of different forms of IBD. A clinical trial evaluated the relationship between MMP and prognosis in CRC. This study enrolled 198 consecutive patients who had undergone operation for CRC, (85 females and 113 males). Of the patient, 67% were older than 65 years old, and their Tumor-Node-Metastasis classification ranged from 1 to 4. Expression of MMPs was higher in tumor tissue than in normal mucosa. This result indicates that high expression of MMP-2 and MMP-9 in the mucosa of CRC patients is related to poorer 5-year survival rates. MMP-7 is implicated in multiple processes of tumor development. To estimate the contribution of serum MMP-7 to the prognosis of resected CRC, researchers have conducted several clinical trials. In a study with 303 CRC patients (87 healthy controls, 96 nonmetastatic patients and 120 advanced patients), high serum MMP-7 was associated with a higher risk of death in terminal CRC patients. Included in another study were 175 curatively resected CRC patients. In two Cox proportional hazard models (overall survival and disease-free survival), higher MMP-7 was associated with higher recurrence and faster progression. Given the role of MMP-3 in cancer progression and metastasis, a study with 73 CRC patients who underwent minimally invasive colorectal resection investigated the relationship between increased plasma MMP-3 and residual metastases after surgery. Minimally invasive surgery directly up-regulated MMP-3 levels owing to surgery or subsequent wound healing or indirectly up-regulated MMP-3 by increasing TNF-α and IL-1 in the acute inflammatory response after surgery.

BAY 12-9566 inhibits MMP-2, MMP-3, and MMP-9. A phase I clinical enrolled 13 patients with colorectal, renal, gastroesophageal junction, duodenum, lung, and sarcoma cancer. Subjects were given BAY 12-9566 at four dosages. No tumor responses were found, but two patients had stable disease after 1.1 and 1.5 years of treatment. In another phase I clinical trial, 27 patients with advanced solid tumors took BAY 12-9566 100 to 1,600 mg/day. These patients had colorectal, lung, breast, ovarian and cervical cancers. The condition of 48% patients was stable. BAY 12-9566 did not reduce the size of the tumor, but slowed their growth. BMS-275291 is another wide-spectrum inhibitor of MMPs. In an open-label, phase I trial, 40 late-stage or metastatic cancer patients were given BMS-275291, most of them had CRC or non-small cell lung cancer. Although the researchers found no objective tumor responses, the condition of some patients stabilized.

Two clinical trials have been conducted on drug combinations. In a randomized, double-blind, clinical trial of rectal cancer, 34 patients receiving chemoradiotherapy were divided into a placebo group and a conjugated linoleic acid group. Supplementing conjugated linoleic acid decreased the levels of TNF-α, IL-1β, hsCRP, MMP-2 and MMP-9, which are biomarkers of tumor aggression and angiogenesis. A trial that included 37 patients with CRC lasted for 7 weeks. These patients who underwent chemotherapy, were separated into two groups: a fisetin group (n=18) and a placebo group (n=19). Flavonoid fisetin reduced levels of MMP-7, and significantly lowered levels of high-sensitivity C-reactive protein and IL-8 by the end of the study.

Despite the important role of MMPs in many human diseases, no broad-spectrum synthetic MMP inhibitor has successfully passed the clinical trial stage because of the bilateral pro-tumor and anti-tumorigenic effects of MMPs in cancer. A variety of MMPs, including MMP-2, MMP-9 and MMP-14, can degrade the basal layer of capillaries and promote exosmosis of tumor cells. MMP-9 also down-regulates the IL receptor on the surface of T cells, further inhibiting immunity and promoting cancer tolerance. By eliminating cell apoptosis, MMP-7 reduces the effect of chemotherapy even promoting tumor growth. However, MMP-8 may directly inhibit tumor metastasis in tumor cells. One of the side effects of broad-spectrum MMP inhibitors is that they interfere with the tumor-inhibiting function of MMP-8. With more specific MMPs inhibitors now available, MMPs targeting can be reconsidered for cancer therapy.

Conclusion

Given their role in degrading the ECM, MMPs are associated with the occurrence and development of many diseases, especially inflammatory diseases. Most MMPs, such as MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, and MMP-13 are increased in colitis and CAC. Therefore, reducing levels of these MMPs could effectively prevent the development of inflammation and CAC, as well as the progression of colitis-the eventual cause of CAC- from acute inflammation to chronic. However, the effect of some MMPs, like MMP-9, on CAC is bidirectional, which means they are involved in the pathogenesis of IBD and promote the metastasis and spread of malignant tumors, but also play a role in tumor suppression as well. Therefore, how to balance the bidirectional role of MMPs in clinical applications is a vital question. In specific diseases, it might be advisable to clarify the therapeutic target, especially the definitive role and efficacy of a certain MMP. Given their multifaceted role in colitis and CAC, more in-depth research is needed. In addition, MMPs participate in the host immune defense, wound healing, and epithelial regeneration. Normally MMPs are secreted and activated in immune cells when the expression of inflammatory cytokines and chemokines increase. MMPs modulate immune system activity by interfering with the differentiation and immune activity of immune cells, recruitment of macrophages, and migration of neutrophils. In clinical trials, the condition of CRC patients could be stabilized to a certain extent by inhibiting levels of MMPs. Therefore, levels of MMPs could be used to predict the condition and development of inflammatory diseases and CAC. Furthermore, MMPs have very broad prospects in the treatment of CAC through immunoregulation, which is also a promising direction in future research.

Author contributions

LH and QK wrote and revised this manuscript. KC constructed figures in manuscript and helped to revise it. YZ helped to revise the manuscript and provided valuable feedback to this conception. ZZ revised the entire manuscript and edited the language for scientific presentation. The corresponding authors, ZZ and WT conceived and organized this study. All authors contributed to the article and approved the submitted version.

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    Not in our library10.1016/j.pcl.2019.06.011

  56. 56.

    Sun L Wang X Saredy J Yuan Z Yang X Wang H. Innate-adaptive immunity interplay and redox regulation in immune response. Redox Biol (2020 ) 37:101759

    Not in our library10.1016/j.redox.2020.101759

  57. 57.

    Arabpour M Saghazadeh A Rezaei N. Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes. Int Immunopharmacol (2021 ) 97:107823

    Not in our library10.1016/j.intimp.2021.107823

  58. 58.

    Tomar N De RK. A brief outline of the immune system. Methods Mol Biol (2014 ) 1184:3–12

    Not in our library10.1007/978-1-4939-1115-8_1

  59. 59.

    Saraiva M O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol (2010 ) 10(3):170–81

    Not in our library10.1038/nri2711

  60. 60.

    Liew PX Kubes P. The neutrophil's role during health and disease. Physiol Rev (2019 ) 99(2):1223–48

    Not in our library10.1152/physrev.00012.2018

  61. 61.

    Shaw DM Merien F Braakhuis A Dulson D. T-Cells and their cytokine production: The anti-inflammatory and immunosuppressive effects of strenuous exercise. Cytokine (2018 ) 104:136–42

    Not in our library10.1016/j.cyto.2017.10.001

  62. 62.

    Karta J Bossicard Y Kotzamanis K Dolznig H Letellier E. Mapping the metabolic networks of tumor cells and cancer-associated fibroblasts. Cells (2021 ) 10(2):304

    Not in our library10.3390/cells10020304

  63. 63.

    Shimoda M Ohtsuka T Okada Y Kanai Y. Stromal metalloproteinases: Crucial contributors to the tumor microenvironment. Pathol Int (2021 ) 71(1):1–14

    Not in our library10.1111/pin.13033

  64. 64.

    Murthy A Shao YW Defamie V Wedeles C Smookler D Khokha R. Stromal TIMP3 regulates liver lymphocyte populations and provides protection against Th1 T cell-driven autoimmune hepatitis. J Immunol (2012 ) 188(6):2876–83

    Not in our library10.4049/jimmunol.1102199

  65. 65.

    Masure S Proost P Van Damme J Opdenakker G. Purification and identification of 91-kDa neutrophil gelatinase. release by the activating peptide interleukin-8. Eur J Biochem (1991 ) 198(2):391–8

    Not in our library10.1111/j.1432-1033.1991.tb16027.x

  66. 66.

    Opdenakker G Van den Steen PE Dubois B Nelissen I Van Coillie E Masure S. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol (2001 ) 69(6):851–9

    Not in our library10.1189/jlb.69.6.851

  67. 67.

    Bar-Or A Nuttall RK Duddy M Alter A Kim HJ Ifergan I. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain (2003 ) 126(Pt 12):2738–49

    Not in our library10.1093/brain/awg285

  68. 68.

    Young J Yu X Wolslegel K Nguyen A Kung C Chiang E. Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis. Cytokine (2010 ) 51(1):78–86

    Not in our library10.1016/j.cyto.2010.03.003

  69. 69.

    Summers deLuca L Gommerman JL. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol (2012 ) 12(5):339–51

    Not in our library10.1038/nri3193

  70. 70.

    Godefroy E Manches O Dréno B Hochman T Rolnitzky L Labarrière N. Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway. Cancer Cell (2011 ) 19(3):333–46

    Not in our library10.1016/j.ccr.2011.01.037

  71. 71.

    Li Q Park PW Wilson CL Parks WC. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell (2002 ) 111(5):635–46

    Not in our library10.1016/s0092-8674(02)01079-6

  72. 72.

    Balbín M Fueyo A Tester AM Pendás AM Pitiot AS Astudillo A. Loss of collagenase-2 confers increased skin tumor susceptibility to Male mice. Nat Genet (2003 ) 35(3):252–7

    Not in our library10.1038/ng1249

  73. 73.

    Palavalli LH Prickett TD Wunderlich JR Wei X Burrell AS Porter-Gill P. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet (2009 ) 41(5):518–20

    Not in our library10.1038/ng.340

  74. 74.
    LPS Responsiveness and Neutrophil Chemotaxis In Vivo Require PMN MMP-8 Activity · 2007
    Corrected
  75. 75.

    Van den Steen PE Proost P Wuyts A Van Damme J Opdenakker G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood (2000 ) 96(8):2673–81

    Not in our library10.1182/blood.v96.8.2673

  76. 76.

    Kessenbrock K Plaks V Werb Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell (2010 ) 141(1):52–67

    Not in our library10.1016/j.cell.2010.03.015

  77. 77.

    Chou J Chan MF Werb Z. Metalloproteinases: A functional pathway for myeloid cells. Microbiol Spectr (2016 ) 4(2):MCHD-0002-2015

    Not in our library10.1128/microbiolspec.mchd-0002-2015

  78. 78.

    Song J Wu C Zhang X Sorokin LM. In vivo processing of CXCL5 (LIX) by matrix metalloproteinase (MMP)-2 and MMP-9 promotes early neutrophil recruitment in IL-1β-induced peritonitis. J Immunol (2013 ) 190(1):401–10

    Not in our library10.4049/jimmunol.1202286

  79. 79.

    Geurts N Becker-Pauly C Martens E Proost P Van den Steen PE Stöcker W. Meprins process matrix metalloproteinase-9 (MMP-9)/gelatinase B and enhance the activation kinetics by MMP-3. FEBS Lett (2012 ) 586(24):4264–9

    Not in our library10.1016/j.febslet.2012.10.033

  80. 80.

    McQuibban GA Gong JH Tam EM McCulloch CA Clark-Lewis I Overall CM. Inflammation dampened by gelatinase a cleavage of monocyte chemoattractant protein-3. Science (2000 ) 289(5482):1202–6

    Not in our library10.1126/science.289.5482.1202

  81. 81.

    Zheng MH Fan Y Smith A Wysocki S Papadimitriou JM Wood DJ. Gene expression of monocyte chemoattractant protein-1 in giant cell tumors of bone osteoclastoma: Possible involvement in CD68+ macrophage-like cell migration. J Cell Biochem (1998 ) 70(1):121–9

    Not in our library10.1002/(sici)1097-4644(19980701)70:1<121::aid-jcb12>3.0.co;2-s

  82. 82.

    Eshghjoo S Kim DM Jayaraman A Sun Y Alaniz RC. Macrophage polarization in atherosclerosis. Genes (2022 ) 13(5):756

    Not in our library10.3390/genes13050756

  83. 83.
    Regulations of Glycolytic Activities on Macrophages Functions in Tumor and Infectious Inflammation · 2020
    Not checked
  84. 84.

    Hingorani DV Lippert CN Crisp JL Savariar EN Hasselmann JPC Kuo C. Impact of MMP-2 and MMP-9 enzyme activity on wound healing, tumor growth and RACPP cleavage. PLos One (2018 ) 13(9):e0198464

    Not in our library10.1371/journal.pone.0198464

  85. 85.

    Clemente C Rius C Alonso-Herranz L Martín-Alonso M Pollán Á Camafeita E. MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis. Nat Commun (2018 ) 9(1):910

    Not in our library10.1038/s41467-018-03351-4

  86. 86.

    Gallazzi M Baci D Mortara L Bosi A Buono G Naselli A. Prostate cancer peripheral blood NK cells show enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 production and secrete monocyte-recruiting and polarizing factors. Front Immunol (2020 ) 11:586126

    Not in our library10.3389/fimmu.2020.586126

  87. 87.
    TIMP3 regulates mammary epithelial apoptosis with immune cell recruitment through differential TNF dependence. · 2011
    Not checked
  88. 88.

    Gordon S Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol (2005 ) 5(12):953–64

    Not in our library10.1038/nri1733

  89. 89.

    Martinez FO Helming L Gordon S. Alternative activation of macrophages: An immunologic functional perspective. Annu Rev Immunol (2009 ) 27:451–83

    Not in our library10.1146/annurev.immunol.021908.132532

  90. 90.

    Parks WC Wilson CL López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol (2004 ) 4(8):617–29

    Not in our library10.1038/nri1418

  91. 91.
    Classical Macrophage Activation Up-Regulates Several Matrix Metalloproteinases through Mitogen Activated Protein Kinases and Nuclear Factor-κB · 2012
    No notice
  92. 92.

    Shimizu K Shichiri M Libby P Lee RT Mitchell RN. Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. J Clin Invest (2004 ) 114(2):300–8

    Not in our library10.1172/jci19855

  93. 93.

    Mosser DM Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol (2008 ) 8(12):958–69

    Not in our library10.1038/nri2448

  94. 94.

    Nathan C Ding A. Nonresolving inflammation. Cell (2010 ) 140(6):871–82

    Not in our library10.1016/j.cell.2010.02.029

  95. 95.

    Fukao T Koyasu S. PI3K and negative regulation of TLR signaling. Trends Immunol (2003 ) 24(7):358–63

    Not in our library10.1016/s1471-4906(03)00139-x

  96. 96.

    Beurel E Michalek SM Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol (2010 ) 31(1):24–31

    Not in our library10.1016/j.it.2009.09.007

  97. 97.

    Shimizu-Hirota R Xiong W Baxter BT Kunkel SL Maillard I Chen X-W. MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev (2012 ) 26(4):395–413

    Not in our library10.1101/gad.178749.111

  98. 98.

    Ramirez-Carrozzi VR Nazarian AA Li CC Gore SL Sridharan R Imbalzano AN. Selective and antagonistic functions of SWI/SNF and Mi-2beta nucleosome remodeling complexes during an inflammatory response. Genes Dev (2006 ) 20(3):282–96

    Not in our library10.1101/gad.1383206

  99. 99.

    Lai D Wan M Wu J Preston-Hurlburt P Kushwaha R Grundström T. Induction of TLR4-target genes entails calcium/calmodulin-dependent regulation of chromatin remodeling. Proc Natl Acad Sci U.S.A. (2009 ) 106(4):1169–74

    Not in our library10.1073/pnas.0811274106

  100. 100.

    Zhou D Collins CA Wu P Brown EJ. Protein tyrosine phosphatase shp-1 positively regulates TLR-induced IL-12p40 production in macrophages through inhibition of phosphatidylinositol 3-kinase. J Leukoc Biol (2010 ) 87(5):845–55

    Not in our library10.1189/jlb.0409289

  101. 101.

    Dean RA Cox JH Bellac CL Doucet A Starr AE Overall CM. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: Potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood (2008 ) 112(8):3455–64

    Not in our library10.1182/blood-2007-12-129080

  102. 102.

    Ganz T. Defensins and host defense. Science (1999 ) 286(5439):420–1

    Not in our library10.1126/science.286.5439.420

  103. 103.

    Yang D Chertov O Oppenheim JJ. Participation of mammalian defensins and cathelicidins in anti-microbial immunity: Receptors and activities of human defensins and cathelicidin (LL-37). J Leukoc Biol (2001 ) 69(5):691–7

    Not in our library10.1189/jlb.69.5.691

  104. 104.

    Ayabe T Satchell DP Wilson CL Parks WC Selsted ME Ouellette AJ. Secretion of microbicidal alpha-defensins by intestinal paneth cells in response to bacteria. Nat Immunol (2000 ) 1(2):113–8

    Not in our library10.1038/77783

  105. 105.

    Murphy CJ Foster BA Mannis MJ Selsted ME Reid TW. Defensins are mitogenic for epithelial cells and fibroblasts. J Cell Physiol (1993 ) 155(2):408–13

    Not in our library10.1002/jcp.1041550223

  106. 106.

    Chen S-Y Zhan X-L Jiang R Dai Y-W Lu J-F Yang G-J. Matrix metalloproteinase-25 from Japanese Sea bass (Lateolabrax japonicus) is involved in pro-inflammatory responses. Dev Comp Immunol (2022 ) 129:104348

    Not in our library10.1016/j.dci.2022.104348

  107. 107.

    Bingle L Brown NJ Lewis CE. The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies. J Pathol (2002 ) 196(3):254–65

    Not in our library10.1002/path.1027

  108. 108.

    Shima T Shimoda M Shigenobu T Ohtsuka T Nishimura T Emoto K. Infiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma. Cancer Sci (2020 ) 111(2):727–38

    Not in our library10.1111/cas.14272

  109. 109.

    Qian B-Z Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell (2010 ) 141(1):39–51

    Not in our library10.1016/j.cell.2010.03.014

  110. 110.

    Agrawal S Anderson P Durbeej M van Rooijen N Ivars F Opdenakker G. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med (2006 ) 203(4):1007–19

    Not in our library10.1084/jem.20051342

  111. 111.

    Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev (2006 ) 25(3):409–16

    Not in our library10.1007/s10555-006-9005-3

  112. 112.

    Manicone AM McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol (2008 ) 19(1):34–41

    Not in our library10.1016/j.semcdb.2007.07.003

  113. 113.

    Lenti M Falcinelli E Pompili M de Rango P Conti V Guglielmini G. Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation. correlation with ischaemic events. Thromb Haemost (2014 ) 111(6):1089–101

    Not in our library10.1160/th13-07-0588

  114. 114.

    Schmidt R Bültmann A Ungerer M Joghetaei N Bülbül O Thieme S. Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: Implications in acute myocardial infarction. Circulation (2006 ) 113(6):834–41

    Not in our library10.1161/circulationaha.105.568162

  115. 115.

    Major TC Liang L Lu X Rosebury W Bocan TMA. Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma. Arterioscler Thromb Vasc Biol (2002 ) 22(7):1200–7

    Not in our library10.1161/01.atv.0000021411.53577.1c

  116. 116.

    Murphy G Hembry RM. Proteinases in rheumatoid arthritis. J Rheumatol Suppl (1992 ) 32:61–4.

    Not in our library

  117. 117.

    Overall CM Wiebkin OW Thonard JC. Demonstration of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva. J Periodontal Res (1987 ) 22(2):81–8

    Not in our library10.1111/j.1600-0765.1987.tb01544.x

  118. 118.
    The Role of Matrix Metalloproteinases in Periodontal Disease · 2020
    No notice
  119. 119.

    Malemud CJ. Matrix metalloproteinases and synovial joint pathology. Prog Mol Biol Transl Sci (2017 ) 148:305–25

    Not in our library10.1016/bs.pmbts.2017.03.003

  120. 120.

    Arai Y Choi B Kim BJ Park S Park H Moon JJ. Cryptic ligand on collagen matrix unveiled by MMP13 accelerates bone tissue regeneration via MMP13/Integrin α3/RUNX2 feedback loop. Acta Biomater (2021 ) 125:219–30

    Not in our library10.1016/j.actbio.2021.02.042

  121. 121.

    Zipfel P Rochais C Baranger K Rivera S Dallemagne P. Matrix metalloproteinases as new targets in Alzheimer’s disease: opportunities and challenges. J Med Chem (2020 ) 63(19):10705–25

    Not in our library10.1021/acs.jmedchem.0c00352

  122. 122.

    Isaacson KJ Martin Jensen M Subrahmanyam NB Ghandehari H. Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression. J Control Release (2017 ) 259:62–75

    Not in our library10.1016/j.jconrel.2017.01.034

  123. 123.

    García-Onrubia L Valentín-Bravo FJ Coco-Martin RM González-Sarmiento R Pastor JC Usategui-Martín R. Matrix metalloproteinases in age-related macular degeneration (AMD). Int J Mol Sci (2020 ) 21(16):5934

    Not in our library10.3390/ijms21165934

  124. 124.

    Chen J Khalil RA. Matrix metalloproteinases in normal pregnancy and preeclampsia. Prog Mol Biol Transl Sci (2017 ) 148:87–165

    Not in our library10.1016/bs.pmbts.2017.04.001

  125. 125.

    Koller FL Dozier EA Nam KT Swee M Birkland TP Parks WC. Lack of MMP10 exacerbates experimental colitis and promotes development of inflammation-associated colonic dysplasia. Lab Invest (2012 ) 92(12):1749–59

    Not in our library10.1038/labinvest.2012.141

  126. 126.

    Brauer R Tureckova J Kanchev I Khoylou M Skarda J Prochazka J. MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function. Mucosal Immunol (2016 ) 9(4):974–85

    Not in our library10.1038/mi.2015.117

  127. 127.

    Jabłońska-Trypuć A Matejczyk M Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhibition Medicinal Chem (2016 ) 31(sup1):177–83

    Not in our library10.3109/14756366.2016.1161620

  128. 128.

    Fischer T Senn N Riedl R. Design and structural evolution of matrix metalloproteinase inhibitors. Chemistry (2019 ) 25(34):7960–80

    Not in our library10.1002/chem.201805361

  129. 129.

    Nagase H Visse R Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res (2006 ) 69(3):562–73

    Not in our library10.1016/j.cardiores.2005.12.002

  130. 130.

    Galis ZS Sukhova GK Kranzhöfer R Clark S Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci U.S.A. (1995 ) 92(2):402–6

    Not in our library10.1073/pnas.92.2.402

  131. 131.

    Kim HE Dalal SS Young E Legato MJ Weisfeldt ML D'Armiento J. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest (2000 ) 106(7):857–66

    Not in our library10.1172/jci8040

  132. 132.

    Klatt AR Paul-Klausch B Klinger G Kühn G Renno JH Banerjee M. A critical role for collagen II in cartilage matrix degradation: Collagen II induces pro-inflammatory cytokines and MMPs in primary human chondrocytes. J Orthopaedic Res (2009 ) 27(1):65–70

    Not in our library10.1002/jor.20716

  133. 133.

    Iimuro Y Nishio T Morimoto T Nitta T Stefanovic B Choi SK. Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat. Gastroenterology (2003 ) 124(2):445–58

    Not in our library10.1053/gast.2003.50063

  134. 134.

    Lombardi R Betocchi S Losi MA Tocchetti CG Aversa M Miranda M. Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation (2003 ) 108(12):1455–60

    Not in our library10.1161/01.cir.0000090687.97972.10

  135. 135.

    García S Forteza J López-Otin C Gómez-Reino JJ González A Conde C. Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model. Arthritis Res Ther (2010 ) 12(6):R224

    Not in our library10.1186/ar3211

  136. 136.

    Cheng C Tempel D van Haperen R van Damme L Algür M Krams R. Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype. Atherosclerosis (2009 ) 204(1):26–33

    Not in our library10.1016/j.atherosclerosis.2009.01.025

  137. 137.

    Quillard T Tesmenitsky Y Croce K Travers R Shvartz E Koskinas KC. Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis. Arterioscler Thromb Vasc Biol (2011 ) 31(11):2464–72

    Not in our library10.1161/atvbaha.111.231563

  138. 138.

    Kim EJ Cho HJ Park D Kim JY Kim YB Park TG. Antifibrotic effect of MMP13-encoding plasmid DNA delivered using polyethylenimine shielded with hyaluronic acid. Mol Ther (2011 ) 19(2):355–61

    Not in our library10.1038/mt.2010.262

  139. 139.

    Gutschalk CM Yanamandra AK Linde N Meides A Depner S Mueller MM. GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression. Cancer Med (2013 ) 2(2):117–29

    Not in our library10.1002/cam4.20

  140. 140.
    Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas · 1999
    No notice
  141. 141.

    Sharshar T Durand MC Lefaucheur JP Lofaso F Raphaël JC Gherardi RK. MMP-9 correlates with electrophysiologic abnormalities in Guillain-Barré syndrome. Neurology (2002 ) 59(10):1649–51

    Not in our library10.1212/01.wnl.0000033799.58866.7a

  142. 142.

    Zhong C Yang J Xu T Xu T Peng Y Wang A. Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke. Neurology (2017 ) 89(8):805–12

    Not in our library10.1212/wnl.0000000000004257

  143. 143.

    Nasr El-Din A Ata KAE Abdel-Gawad AR Fahmy NF. Impact of high serum levels of MMP-7, MMP-9, TGF-β and PDGF macrophage activation markers on severity of COVID-19 in obese-diabetic patients. Infection Drug Resistance (2021 ) 14:4015–25

    Not in our library10.2147/idr.s329004

  144. 144.

    Frieling JS Li T Tauro M Lynch CC. Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis. Neoplasia (2020 ) 22(10):511–21

    Not in our library10.1016/j.neo.2020.08.004

  145. 145.

    Bauer A Habior A. Concentration of serum matrix metalloproteinase-3 in patients with primary biliary cholangitis. Front Immunol (2022 ) 13:885229

    Not in our library10.3389/fimmu.2022.885229

  146. 146.

    Matilla L Roncal C Ibarrola J Arrieta V García-Peña A Fernández-Celis A. A role for MMP-10 (Matrix metalloproteinase-10) in calcific aortic valve stenosis. Arterioscler Thromb Vasc Biol (2020 ) 40(5):1370–82

    Not in our library10.1161/atvbaha.120.314143

  147. 147.

    Frederick LA Matthews JA Jamieson L Justilien V Thompson EA Radisky DC. Matrix metalloproteinase-10 is a critical effector of protein kinase Ciota-Par6alpha-Mediated lung cancer. Oncogene (2008 ) 27(35):4841–53

    Not in our library10.1038/onc.2008.119

  148. 148.

    Cheng CW Yu JC Wang HW Huang CS Shieh JC Fu YP. The clinical implications of MMP-11 and CK-20 expression in human breast cancer. Clinica Chimica Acta (2010 ) 411(3-4):234–41

    Not in our library10.1016/j.cca.2009.11.009

  149. 149.

    Tian X Ye C Yang Y Guan X Dong B Zhao M. Expression of CD147 and matrix metalloproteinase-11 in colorectal cancer and their relationship to clinicopathological features. J Trans Med (2015 ) 13:337

    Not in our library10.1186/s12967-015-0702-y

  150. 150.

    Acioglu E Yigit O Alkan Z Server EA Uzun H Gelisgen R. The role of matrix metalloproteinases in recurrent tonsillitis. Int J Pediatr Otorhinolaryngol (2010 ) 74(5):535–9

    Not in our library10.1016/j.ijporl.2010.02.016

  151. 151.

    Hsu TI Lin SC Lu PS Chang WC Hung CY Yeh YM. MMP-7-mediated cleavage of nucleolin at ASP255 induces MMP9 expression to promote tumor malignancy. Oncogene (2015 ) 34(7):826–37

    Not in our library10.1038/onc.2014.22

  152. 152.

    Hu BH Cai Q Hu Z Patel M Bard J Jamison J. Metalloproteinases and their associated genes contribute to the functional integrity and noise-induced damage in the cochlear sensory epithelium. J Neurosci (2012 ) 32(43):14927–41

    Not in our library10.1523/jneurosci.1588-12.2012

  153. 153.

    Soslow JH Xu M Slaughter JC Crum K Chew JD Burnette WB. The role of matrix metalloproteinases and tissue inhibitors of metalloproteinases in duchenne muscular dystrophy cardiomyopathy. J Cardiac Failure (2019 ) 25(4):259–67

    Not in our library10.1016/j.cardfail.2019.02.006

  154. 154.

    Buhler LA Samara R Guzman E Wilson CL Krizanac-Bengez L Janigro D. Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis. BMC Neurosci (2009 ) 10:17

    Not in our library10.1186/1471-2202-10-17

  155. 155.

    Harada T Arii S Mise M Imamura T Higashitsuji H Furutani M. Membrane-type matrix metalloproteinase-1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol (1998 ) 28(2):231–9

    Not in our library10.1016/0168-8278(88)80010-2

  156. 156.

    Li T Xie J Shen C Cheng D Shi Y Wu Z. miR-150-5p inhibits hepatoma cell migration and invasion by targeting MMP14. PLos One (2014 ) 9(12):e115577

    Not in our library10.1371/journal.pone.0115577

  157. 157.

    Kurahara S Shinohara M Ikebe T Nakamura S Beppu M Hiraki A. Expression of MMPs, MT-MMP, and TIMPs in squamous cell carcinoma of the oral cavity: Correlations with tumor invasion and metastasis. Head Neck (1999 ) 21(7):627–38

    Not in our library10.1002/(sici)1097-0347(199910)21:7<627::aid-hed7>3.0.co;2-2

  158. 158.

    Mimori K Fukagawa T Kosaka Y Ishikawa K Iwatsuki M Yokobori T. A Large-scale study of MT1-MMP as a marker for isolated tumor cells in peripheral blood and bone marrow in gastric cancer cases. Ann Surg Oncol (2008 ) 15(10):2934–42

    Not in our library10.1245/s10434-008-9916-z

  159. 159.

    Xu X Chen L Xu B Xie Q Sun M Deng X. Increased MT2-MMP expression in gastric cancer patients is associated with poor prognosis. Int J Clin Exp Pathol (2015 ) 8(2):1985–90.

    Not in our library

  160. 160.

    Jalali S Singh S Agnihotri S Wataya T Salehi F Alkins R. A role for matrix remodelling proteins in invasive and malignant meningiomas. Neuropathol Appl Neurobiol (2015 ) 41(2):e16–28

    Not in our library10.1111/nan.12166

  161. 161.

    Chabottaux V Sounni NE Pennington CJ English WR van den Brûle F Blacher S. Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases. Cancer Res (2006 ) 66(10):5165–72

    Not in our library10.1158/0008-5472.can-05-3012

  162. 162.

    Baranger K Bonnet AE Girard SD Paumier JM García-González L Elmanaa W. MT5-MMP promotes Alzheimer’s pathogenesis in the frontal cortex of 5xFAD mice and app trafficking in vitro. Front Mol Neurosci (2016 ) 9:163

    Not in our library10.3389/fnmol.2016.00163

  163. 163.

    Baranger K Marchalant Y Bonnet AE Crouzin N Carrete A Paumier JM. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer’s disease. Cell Mol Life Sci (2016 ) 73(1):217–36

    Not in our library10.1007/s00018-015-1992-1

  164. 164.

    Pilat D Paumier JM García-González L Louis L Stephan D Manrique C. MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer’s disease. J Neuroinflamm (2022 ) 19(1):65

    Not in our library10.1186/s12974-022-02407-z

  165. 165.

    Sugimoto W Itoh K Hirata H Abe Y Torii T Mitsui Y. MMP24 as a target of YAP is a potential prognostic factor in cancer patients. Bioengineering (2020 ) 7(1):18

    Not in our library10.3390/bioengineering7010018

  166. 166.

    Velasco G Cal S Merlos-Suárez A Ferrando AA Alvarez S Nakano A. Human MT6-matrix metalloproteinase: Identification, progelatinase a activation, and expression in brain tumors. Cancer Res (2000 ) 60(4):877–82.

    Not in our library

  167. 167.

    López B González A Díez J. Circulating biomarkers of collagen metabolism in cardiac diseases. Circulation (2010 ) 121(14):1645–54

    Not in our library10.1161/circulationaha.109.912774

  168. 168.

    Choke E Cockerill G Wilson WR Sayed S Dawson J Loftus I. A review of biological factors implicated in abdominal aortic aneurysm rupture. Eur J Vasc Endovascular Surg (2005 ) 30(3):227–44

    Not in our library10.1016/j.ejvs.2005.03.009

  169. 169.

    Van den Steen PE Dubois B Nelissen I Rudd PM Dwek RA Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol (2002 ) 37(6):375–536

    Not in our library10.1080/10409230290771546

  170. 170.

    Ram M Sherer Y Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol (2006 ) 26(4):299–307

    Not in our library10.1007/s10875-006-9022-6

  171. 171.

    Overall CM López-Otín C. Strategies for MMP inhibition in cancer: Innovations for the post-trial era. Nat Rev Cancer (2002 ) 2(9):657–72

    Not in our library10.1038/nrc884

  172. 172.

    Ahmed AS Li J Erlandsson-Harris H Stark A Bakalkin G Ahmed M. Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis. Pain (2012 ) 153(1):18–26

    Not in our library10.1016/j.pain.2011.08.001

  173. 173.

    Mittal R Patel AP Debs LH Nguyen D Patel K Mh G. Intricate functions of matrix metalloproteinases in physiological and pathological conditions. J Cell Physiol (2016 ) 231(12):2599–621

    Not in our library10.1002/jcp.25430

  174. 174.

    Puente XS Pendás AM Llano E Velasco G López-Otín C. Molecular cloning of a novel membrane-type matrix metalloproteinase from a human breast carcinoma. Cancer Res (1996 ) 56(5):944–9.

    Not in our library

  175. 175.
    The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases · 2020
    No notice
  176. 176.
    Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics · 2020
    No notice
  177. 177.

    Peschon JJ Slack JL Reddy P Stocking KL Sunnarborg SW Lee DC. An essential role for ectodomain shedding in mammalian development. Science (1998 ) 282(5392):1281–4

    Not in our library10.1126/science.282.5392.1281

  178. 178.

    Strand S Vollmer P van den Abeelen L Gottfried D Alla V Heid H. Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells. Oncogene (2004 ) 23(20):3732–6

    Not in our library10.1038/sj.onc.1207387

  179. 179.

    Ahonen M Poukkula M Baker AH Kashiwagi M Nagase H Eriksson JE. Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene (2003 ) 22(14):2121–34

    Not in our library10.1038/sj.onc.1206292

  180. 180.

    Chun TH Sabeh F Ota I Murphy H McDonagh KT Holmbeck K. MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix. J Cell Biol (2004 ) 167(4):757–67

    Not in our library10.1083/jcb.200405001

  181. 181.

    Stratman AN Saunders WB Sacharidou A Koh W Fisher KE Zawieja DC. Endothelial cell lumen and vascular guidance tunnel formation requires MT1-MMP-dependent proteolysis in 3-dimensional collagen matrices. Blood (2009 ) 114(2):237–47

    Not in our library10.1182/blood-2008-12-196451

  182. 182.

    Rundhaug JE. Matrix metalloproteinases, angiogenesis, and cancer: Commentary re: A. c. Lockhart et al., reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clin Cancer Res (2003 ) 9(2):551–4

    Not in our library10.1093/carcin/24.2.343

  183. 183.

    Ghasemi A Hashemy SI Aghaei M Panjehpour M. Leptin induces matrix metalloproteinase 7 expression to promote ovarian cancer cell invasion by activating ERK and JNK pathways. J Cell Biochem (2018 ) 119(2):2333–44

    Not in our library10.1002/jcb.26396

  184. 184.
    Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective Strategies with Phytochemicals · 2015
    No notice
  185. 185.

    Cui Q Wang B Li K Sun H Hai T Zhang Y. Upregulating MMP-1 in carcinoma-associated fibroblasts reduces the efficacy of Taxotere on breast cancer synergized by Collagen IV. Oncol Lett (2018 ) 16(3):3537–44

    Not in our library10.3892/ol.2018.9092

  186. 186.

    Wang QM Lv L Tang Y Zhang L Wang LF. MMP-1 is overexpressed in triple-negative breast cancer tissues and the knockdown of MMP-1 expression inhibits tumor cell malignant behaviors in vitro. Oncol Lett (2019 ) 17(2):1732–40

    Not in our library10.3892/ol.2018.9779

  187. 187.

    Yamada T Oshima T Yoshihara K Tamura S Kanazawa A Inagaki D. Overexpression of MMP-13 gene in colorectal cancer with liver metastasis. Anticancer Res (2010 ) 30(7):2693–9

    Not in our library10.1097/cad.0b013e32833ab7a0

  188. 188.

    Zhang X Huang S Guo J Zhou L You L Zhang T. Insights into the distinct roles of MMP-11 in tumor biology and future therapeutics (Review). Int J Oncol (2016 ) 48(5):1783–93

    Not in our library10.3892/ijo.2016.3400

  189. 189.

    Knapinska AM Fields GB. The expanding role of MT1-MMP in cancer progression. Pharmaceuticals (2019 ) 12(2):77

    Not in our library10.3390/ph12020077

  190. 190.

    Gialeli C Theocharis AD Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J (2011 ) 278(1):16–27

    Not in our library10.1111/j.1742-4658.2010.07919.x

  191. 191.
    Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1 · 2020
    No notice
  192. 192.

    Wells JM Gaggar A Blalock JE. MMP generated matrikines. Matrix Biol (2015 ) 44-46:122–9

    Not in our library10.1016/j.matbio.2015.01.016

  193. 193.
    Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression · 2021
    No notice
  194. 194.
    A pan-cancer perspective of matrix metalloproteases (MMP) gene expression profile and their diagnostic/prognostic potential · 2019
    No notice
  195. 195.

    Buttacavoli M Di Cara G Roz E Pucci-Minafra I Feo S Cancemi P. Integrated multi-omics investigations of metalloproteinases in colon cancer: Focus on MMP2 and MMP9. Int J Mol Sci (2021 ) 22(22):12389

    Not in our library10.3390/ijms222212389

  196. 196.

    Leifler KS Svensson S Abrahamsson A Bendrik C Robertson J Gauldie J. Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer. J Immunol (2013 ) 190(8):4420–30

    Not in our library10.4049/jimmunol.1202610

  197. 197.

    Heimesaat MM Dunay IR Fuchs D Trautmann D Fischer A Kühl AA. The distinct roles of MMP-2 and MMP-9 in acute DSS colitis. Eur J Microbiol Immunol (2011 ) 1(4):302–10

    Not in our library10.1556/eujmi.1.2011.4.6

  198. 198.

    Lin X Li J Zhao Q Feng JR Gao Q Nie JY. WGCNA reveals key roles of IL8 and MMP-9 in progression of involvement area in colon of patients with ulcerative colitis. Curr Med Sci (2018 ) 38(2):252–8

    Not in our library10.1007/s11596-018-1873-6

  199. 199.

    Zeng Y Gao M Lin D Du G Cai Y. Prognostic and immunological roles of MMP-9 in pan-cancer. BioMed Res Int (2022 ) 2022:2592962

    Not in our library10.1155/2022/2592962

  200. 200.

    Wu J Chen Z Wickström SL Gao J He X Jing X. Interleukin-33 is a novel immunosuppressor that protects cancer cells from TIL killing by a macrophage-mediated shedding mechanism. Advanced Sci (2021 ) 8(21):e2101029

    Not in our library10.1002/advs.202101029

  201. 201.

    Kim HS Kim MG Min KW Jung US Kim DH. High MMP-11 expression associated with low CD8+ T cells decreases the survival rate in patients with breast cancer. PLos One (2021 ) 16(5):e0252052

    Not in our library10.1371/journal.pone.0252052

  202. 202.

    Fingleton B. Matrix metalloproteinases as regulators of inflammatory processes. Biochim Biophys Acta Mol Cell Res (2017 ) 1864(11 Pt A):2036–42

    Not in our library10.1016/j.bbamcr.2017.05.010

  203. 203.

    McMahan RS Birkland TP Smigiel KS Vandivort TC Rohani MG Manicone AM. Stromelysin-2 (MMP10) moderates inflammation by controlling macrophage activation. J Immunol (2016 ) 197(3):899–909

    Not in our library10.4049/jimmunol.1600502

  204. 204.

    Baugh MD Perry MJ Hollander AP Davies DR Cross SS Lobo AJ. Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology (1999 ) 117(4):814–22

    Not in our library10.1016/s0016-5085(99)70339-2

  205. 205.

    von Lampe B Barthel B Coupland SE Riecken EO Rosewicz S. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut (2000 ) 47(1):63–73

    Not in our library10.1136/gut.47.1.63

  206. 206.

    Matsuno K Adachi Y Yamamoto H Goto A Arimura Y Endo T. The expression of matrix metalloproteinase matrilysin indicates the degree of inflammation in ulcerative colitis. J Gastroenterol (2003 ) 38(4):348–54

    Not in our library10.1007/s005350300062

  207. 207.

    Saarialho-Kere UK Vaalamo M Puolakkainen P Airola K Parks WC Karjalainen-Lindsberg ML. Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. Am J Pathol (1996 ) 148(2):519–26

    Not in our library10.1111/j.1399-0039.1996.tb02552.x

  208. 208.

    Sánchez K Maguire-Zeiss K. MMP13 expression is increased following mutant α-synuclein exposure and promotes inflammatory responses in microglia. Front Neurosci (2020 ) 14:585544

    Not in our library10.3389/fnins.2020.585544

  209. 209.

    Le NTV Xue M Castelnoble LA Jackson CJ. The dual personalities of matrix metalloproteinases in inflammation. Front Biosci (2007 ) 12:1475–87

    Not in our library10.2741/2161

  210. 210.

    Vanlaere I Libert C. Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock. Clin Microbiol Rev (2009 ) 22(2):224–39

    Not in our library10.1128/cmr.00047-08

  211. 211.

    Tressel SL Kaneider NC Kasuda S Foley C Koukos G Austin K. A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol Med (2011 ) 3(7):370–84

    Not in our library10.1002/emmm.201100145

  212. 212.

    Walter L Canup B Pujada A Bui TA Arbasi B Laroui H. Matrix metalloproteinase 9 (MMP9) limits reactive oxygen species (ROS) accumulation and DNA damage in colitis-associated cancer. Cell Death Dis (2020 ) 11(9):767

    Not in our library10.1038/s41419-020-02959-z

  213. 213.

    Garg P Sarma D Jeppsson S Patel NR Gewirtz AT Merlin D. Matrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancer. Cancer Res (2010 ) 70(2):792–801

    Not in our library10.1158/0008-5472.can-09-3166

  214. 214.

    Goel GA Kandiel A Achkar JP Lashner B. Molecular pathways underlying IBD-associated colorectal neoplasia: Therapeutic implications. Am J Gastroenterol (2011 ) 106(4):719–30

    Not in our library10.1038/ajg.2011.51

  215. 215.

    OʼShea NR Smith AM. Matrix metalloproteases role in bowel inflammation and inflammatory bowel disease: An up to date review. Inflammation Bowel Dis (2014 ) 20(12):2379–93

    Not in our library10.1097/mib.0000000000000163

  216. 216.

    Medina C Videla S Radomski A Radomski MW Antolín M Guarner F. Increased activity and expression of matrix metalloproteinase-9 in a rat model of distal colitis. Am J Physiol Gastrointestinal Liver Physiol (2003 ) 284(1):G116–22

    Not in our library10.1152/ajpheart.00036.2002

  217. 217.

    Ravi A Garg P Sitaraman SV. Matrix metalloproteinases in inflammatory bowel disease: Boon or a bane? Inflamm Bowel Dis (2007 ) 13(1):97–107

    Not in our library10.1002/ibd.20011

  218. 218.

    Gao Q Meijer MJW Kubben FJGM Sier CFM Kruidenier L van Duijn W. Expression of matrix metalloproteinases-2 and -9 in intestinal tissue of patients with inflammatory bowel diseases. Digestive Liver Dis (2005 ) 37(8):584–92

    Not in our library10.1016/j.dld.2005.02.011

  219. 219.

    Medina C Santana A Paz-Cabrera MC Parra-Blanco A Nicolás D Gimeno-Garcia AZ. Increased activity and expression of gelatinases in ischemic colitis. Dig Dis Sci (2006 ) 51(12):2393–9

    Not in our library10.1007/s10620-006-9255-5

  220. 220.
    Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer · 2015
    No notice
  221. 221.

    Kusugami K Nobata K Tsuzuki T Ando T Ina K. Mucosal expression of matrix metalloproteinases and their tissue inhibitors in ulcerative colitis patients. J Gastroenterol (2003 ) 38(4):412–3

    Not in our library10.1007/s005350300075

  222. 222.

    Pender SL Tickle SP Docherty AJ Howie D Wathen NC MacDonald TT. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol (1997 ) 158(4):1582–90.

    Not in our library

  223. 223.

    Pender SL Fell JM Chamow SM Ashkenazi A MacDonald TT. A P55 TNF receptor immunoadhesin prevents T cell-mediated intestinal injury by inhibiting matrix metalloproteinase production. J Immunol (1998 ) 160(8):4098–103

    Not in our library10.4049/jimmunol.160.8.4098

  224. 224.

    Kirkegaard T Hansen A Bruun E Brynskov J. Expression and localisation of matrix metalloproteinases and their natural inhibitors in fistulae of patients with Crohn's disease. Gut (2004 ) 53(5):701–9

    Not in our library10.1136/gut.2003.017442

  225. 225.

    Pilcher BK Dumin JA Sudbeck BD Krane SM Welgus HG Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol (1997 ) 137(6):1445–57

    Not in our library10.1083/jcb.137.6.1445

  226. 226.

    Salmela MT Pender SLF Karjalainen-Lindsberg ML Puolakkainen P Macdonald TT Saarialho-Kere U. Collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and stromelysin-2 (MMP-10) are expressed by migrating enterocytes during intestinal wound healing. Scand J Gastroenterol (2004 ) 39(11):1095–104

    Not in our library10.1080/00365520410003470

  227. 227.

    Gill SE Parks WC. Metalloproteinases and their inhibitors: Regulators of wound healing. Int J Biochem Cell Biol (2008 ) 40(6-7):1334–47

    Not in our library10.1016/j.biocel.2007.10.024

  228. 228.

    Hayden DM Forsyth C Keshavarzian A. The role of matrix metalloproteinases in intestinal epithelial wound healing during normal and inflammatory states. J Surg Res (2011 ) 168(2):315–24

    Not in our library10.1016/j.jss.2010.03.002

  229. 229.

    Bamba S Andoh A Yasui H Araki Y Bamba T Fujiyama Y. Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: Role of interleukin-17. J Gastroenterol (2003 ) 38(6):548–54

    Not in our library10.1007/s00535-002-1101-8

  230. 230.

    Bullard KM Mudgett J Scheuenstuhl H Hunt TK Banda MJ. Stromelysin-1-deficient fibroblasts display impaired contraction in vitro. J Surg Res (1999 ) 84(1):31–4

    Not in our library10.1006/jsre.1999.5599

  231. 231.

    Bullard KM Lund L Mudgett JS Mellin TN Hunt TK Murphy B. Impaired wound contraction in stromelysin-1-deficient mice. Ann Surg (1999 ) 230(2):260–5

    Not in our library10.1097/00000658-199908000-00017

  232. 232.

    Nissinen L Kähäri V-M. Matrix metalloproteinases in inflammation. Biochim Biophys Acta (2014 ) 1840(8):2571–80

    Not in our library10.1016/j.bbagen.2014.03.007

  233. 233.

    Butler GS Overall CM. Matrix metalloproteinase processing of signaling molecules to regulate inflammation. Periodontol 2000 (2013 ) 63(1):123–48

    Not in our library10.1111/prd.12035

  234. 234.

    McQuibban GA Butler GS Gong JH Bendall L Power C Clark-Lewis I. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem (2001 ) 276(47):43503–8

    Not in our library10.1074/jbc.m107736200

  235. 235.

    McQuibban GA Gong J-H Wong JP Wallace JL Clark-Lewis I Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood (2002 ) 100(4):1160–7

    Not in our library10.1182/blood.v100.4.1160.h81602001160_1160_1167

  236. 236.

    Van Den Steen PE Wuyts A Husson SJ Proost P Van Damme J Opdenakker G. Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCl6, ENA-78/CXCl5 and mouse GCP-2/LIX and modulate their physiological activities. Eur J Biochem (2003 ) 270(18):3739–49

    Not in our library10.1046/j.1432-1033.2003.03760.x

  237. 237.

    Starr AE Dufour A Maier J Overall CM. Biochemical analysis of matrix metalloproteinase activation of chemokines CCL15 and CCL23 and increased glycosaminoglycan binding of CCL16. J Biol Chem (2012 ) 287(8):5848–60

    Not in our library10.1074/jbc.m111.314609

  238. 238.

    Haro H Crawford HC Fingleton B Shinomiya K Spengler DM Matrisian LM. Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. J Clin Invest (2000 ) 105(2):143–50

    Not in our library10.1172/jci7091

  239. 239.

    McCawley LJ Matrisian LM. Matrix metalloproteinases: They're not just for matrix anymore! Curr Opin Cell Biol (2001 ) 13(5):534–40

    Not in our library10.1016/s0955-0674(00)00248-9

  240. 240.

    Schönbeck U Mach F Libby P. Generation of biologically active IL-1 beta by matrix metalloproteinases: A novel caspase-1-dependent pathway of IL-1 beta processing. J Immunol (1998 ) 161(7):3340–6

    Not in our library10.4049/jimmunol.161.7.3340

  241. 241.

    Ito A Mukaiyama A Itoh Y Nagase H Thogersen IB Enghild JJ. Degradation of interleukin 1beta by matrix metalloproteinases. J Biol Chem (1996 ) 271(25):14657–60

    Not in our library10.1074/jbc.271.25.14657

  242. 242.

    Hosokawa Y Hosokawa I Ozaki K Matsuo T. Sudachitin inhibits matrix metalloproteinase-1 and -3 production in tumor necrosis factor-α-stimulated human periodontal ligament cells. Inflammation (2019 ) 42(4):1456–62

    Not in our library10.1007/s10753-019-01007-z

  243. 243.

    Ahn S-J Rhim E-M Kim J-Y Kim K-H Lee H-W Kim E-C. Tumor necrosis factor-α induces matrix metalloproteinases-3, -10, and -13 in human periodontal ligament cells. J Periodontol (2014 ) 85(3):490–7

    Not in our library10.1902/jop.2013.130063

  244. 244.

    Du G Liu C Li X Chen W He R Wang X. Induction of matrix metalloproteinase-1 by tumor necrosis factor-α is mediated by interleukin-6 in cultured fibroblasts of keratoconus. Exp Biol Med (2016 ) 241(18):2033–41

    Not in our library10.1177/1535370216650940

  245. 245.

    Castaneda FE Walia B Vijay-Kumar M Patel NR Roser S Kolachala VL. Targeted deletion of metalloproteinase 9 attenuates experimental colitis in mice: Central role of epithelial-derived MMP. Gastroenterology (2005 ) 129(6):1991–2008

    Not in our library10.1053/j.gastro.2005.09.017

  246. 246.

    Mimura T Bateman AC Lee RL Johnson PA McDonald PJ Talbot IC. Up-regulation of collagen and tissue inhibitors of matrix metalloproteinase in colonic diverticular disease. Dis Colon Rectum (2004 ) 47(3):371–8

    Not in our library10.1007/s10350-003-0050-5

  247. 247.

    Bister V Salmela MT Heikkilä P Anttila A Rintala R Isaka K. Matrilysins-1 and -2 (MMP-7 and -26) and metalloelastase (MMP-12), unlike MMP-19, are up-regulated in necrotizing enterocolitis. J Pediatr Gastroenterol Nutr (2005 ) 40(1):60–6

    Not in our library10.1097/00005176-200501000-00011

  248. 248.

    Hasty KA Pourmotabbed TF Goldberg GI Thompson JP Spinella DG Stevens RM. Human neutrophil collagenase. a distinct gene product with homology to other matrix metalloproteinases. J Biol Chem (1990 ) 265(20):11421–4

    Not in our library10.4049/jimmunol.161.7.3340

  249. 249.

    Houghton AM Hartzell WO Robbins CS Gomis-Rüth FX Shapiro SD. Macrophage elastase kills bacteria within murine macrophages. Nature (2009 ) 460(7255):637–41

    Not in our library10.1038/nature08181

  250. 250.

    Wilson CL Ouellette AJ Satchell DP Ayabe T López-Boado YS Stratman JL. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science (1999 ) 286(5437):113–7

    Not in our library10.1126/science.286.5437.113

  251. 251.

    Pal S Schmidt AP Peterson EM Wilson CL de la Maza LM. Role of matrix metalloproteinase-7 in the modulation of a chlamydia trachomatis infection. Immunology (2006 ) 117(2):213–9

    Not in our library10.1111/j.1365-2567.2005.02281.x

  252. 252.

    Esteban S Clemente C Koziol A Gonzalo P Rius C Martínez F. Endothelial MT1-MMP targeting limits intussusceptive angiogenesis and colitis via TSP1/Nitric oxide axis. EMBO Mol Med (2020 ) 12(2):e10862

    Not in our library10.15252/emmm.201910862

  253. 253.

    Marelli G Erreni M Anselmo A Taverniti V Guglielmetti S Mantovani A. Heme-Oxygenase-1 production by intestinal CX3CR1 macrophages helps to resolve inflammation and prevents carcinogenesis. Cancer Res (2017 ) 77(16):4472–85

    Not in our library10.1158/0008-5472.can-16-2501

  254. 254.

    Medina-Contreras O Geem D Laur O Williams IR Lira SA Nusrat A. CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest (2011 ) 121(12):4787–95

    Not in our library10.1172/jci59150

  255. 255.

    Zhuang Q Ou J Zhang S Ming Y. Crosstalk between the CX3CL1/CX3CR1 axis and inflammatory signaling pathways in tissue injury. Curr Protein Pept Sci (2019 ) 20(8):844–54

    Not in our library10.2174/1389203720666190305165722

  256. 256.

    de Bruyn M Arijs I Wollants WJ Machiels K Van Steen K Van Assche G. Neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 complex as a surrogate serum marker of mucosal healing in ulcerative colitis. Inflamm Bowel Dis (2014 ) 20(7):1198–207

    Not in our library10.1097/mib.0000000000000068

  257. 257.

    Farkas K Saródi Z Bálint A Földesi I Tiszlavicz L Szűcs M. The diagnostic value of a new fecal marker, matrix metalloprotease-9, in different types of inflammatory bowel diseases. J Crohns Colitis (2015 ) 9(3):231–7

    Not in our library10.1093/ecco-jcc/jjv005

  258. 258.

    Annaházi A Molnár T Farkas K Rosztóczy A Izbéki F Gecse K. Fecal MMP-9: A new noninvasive differential diagnostic and activity marker in ulcerative colitis. Inflamm Bowel Dis (2013 ) 19(2):316–20

    Not in our library10.1002/ibd.22996

  259. 259.

    Faubion WA Jr. Fletcher JG O'Byrne S Feagan BG de Villiers WJ Salzberg B. Emerging BiomARKers in inflammatory bowel disease (EMBARK) study identifies fecal calprotectin, serum MMP9, and serum IL-22 as a novel combination of biomarkers for Crohn's disease activity: Role of cross-sectional imaging. Am J Gastroenterol (2013 ) 108(12):1891–900

    Not in our library10.1038/ajg.2013.354

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    Naito Y Yoshikawa T. Role of matrix metalloproteinases in inflammatory bowel disease. Mol Aspects Med (2005 ) 26(4-5):379–90

    Not in our library10.1016/j.mam.2005.07.009

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    Langholz E Munkholm P Davidsen M Binder V. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology (1992 ) 103(5):1444–51

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    Prior P Fielding JF Waterhouse JA Cooke WT. Mortality in Crohn's disease. Lancet (1970 ) 1(7657):1135–7

    Not in our library10.1016/s0140-6736(70)91213-4

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    Xue M Shi L Wang W Chen S Wang L. An overview of molecular profiles in ulcerative colitis-related cancer. Inflammation Bowel Dis (2018 ) 24(9):1883–94

    Not in our library10.1093/ibd/izy221

  264. 264.

    Baek S-J Kim S-H. Colitis-associated colorectal cancer in patients with inflammatory bowel disease. Minerva Chir (2017 ) 72(6):520–9

    Not in our library10.23736/s0026-4733.17.07437-5

  265. 265.

    Shah SC Itzkowitz SH. Colorectal cancer in inflammatory bowel disease: Mechanisms and management. Gastroenterology (2022 ) 162(3):715–30.e3

    Not in our library10.1053/j.gastro.2021.10.035

  266. 266.

    Itzkowitz SH Yio X. Inflammation and Cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol (2004 ) 287(1):G7–17

    Not in our library10.1152/ajpgi.00079.2004

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    Short SP Pilat JM Barrett CW Reddy VK Haberman Y Hendren JR. Colonic epithelial-derived Selenoprotein P is the source for antioxidant-mediated protection in colitis-associated cancer. Gastroenterology (2021 ) 160(5):1694–708.e3

    Not in our library10.1053/j.gastro.2020.12.059

  268. 268.

    Garg P Jeppsson S Dalmasso G Ghaleb AM McConnell BB Yang VW. Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice. Gastroenterology (2011 ) 141(4):1381–92

    Not in our library10.1053/j.gastro.2011.06.056

  269. 269.

    Cadet J Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol (2013 ) 5(2):a012559

    Not in our library10.1101/cshperspect.a012559

  270. 270.

    Peng K Kou L Yu L Bai C Li M Mo P. Histone demethylase JMJD2D interacts with β-catenin to induce transcription and activate colorectal cancer cell proliferation and tumor growth in mice. Gastroenterology (2019 ) 156(4):1112–26

    Not in our library10.1053/j.gastro.2018.11.036

  271. 271.

    Oshima H Nakayama M Han TS Naoi K Ju X Maeda Y. Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. Cancer Res (2015 ) 75(4):766–76

    Not in our library10.1158/0008-5472.can-14-2036

  272. 272.

    Yoo J Rodriguez Perez CE Nie W Sinnett-Smith J Rozengurt E. Protein kinase D1 mediates synergistic MMP-3 expression induced by TNF-α and bradykinin in human colonic myofibroblasts. Biochem Biophys Res Commun (2011 ) 413(1):30–5

    Not in our library10.1016/j.bbrc.2011.08.029

  273. 273.

    Adegboyega PA Ololade O Saada J Mifflin R Di Mari JF Powell DW. Subepithelial myofibroblasts express cyclooxygenase-2 in colorectal tubular adenomas. Clin Cancer Res (2004 ) 10(17):5870–9

    Not in our library10.1158/1078-0432.ccr-0431-03

  274. 274.

    Cheng SM Xing B Li JC Cheung BK Lau AS. Interferon-gamma regulation of TNF alpha-induced matrix metalloproteinase 3 expression and migration of human glioma T98G cells. Int J Cancer (2007 ) 121(6):1190–6

    Not in our library10.1002/ijc.22729

  275. 275.

    Newell KJ Matrisian LM Driman DK. Matrilysin (Matrix metalloproteinase-7) expression in ulcerative colitis-related tumorigenesis. Mol Carcinog (2002 ) 34(2):59–63

    Not in our library10.1002/mc.10049

  276. 276.

    Walter L Harper C Garg P. Role of matrix metalloproteinases in Inflammation/Colitis-associated colon cancer. ImmunoGastroenterology (2013 ) 2(2):22–2822

    Not in our library10.7178/ig.29

  277. 277.

    Ou Y-r Jing G-y Wu Q Gao S Cheng Z-n Dong X-q. Expression of Tcf-4, MMP-7 and survivin in colorectal cancer and its clinical significance. J Sichuan Univ Med Sci Edition (2015 ) 46(4):554–9.

    Not in our library

  278. 278.

    Bai YP Shang K Chen H Ding F Wang Z Liang C. FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through ERK and MMP-7. Cancer Sci (2015 ) 106(10):1278–87

    Not in our library10.1111/cas.12745

  279. 279.

    Walter L Pujada A Bhatnagar N Bialkowska AB Yang VW Laroui H. Epithelial derived-matrix metalloproteinase (MMP9) exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-P53 axis. Oncotarget (2017 ) 8(1):364–78

    Not in our library10.18632/oncotarget.13406

  280. 280.

    Pozzi A LeVine WF Gardner HA. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene (2002 ) 21(2):272–81

    Not in our library10.1038/sj.onc.1205045

  281. 281.
    MMP9 is protective against lethal inflammatory mass lesions in the mouse colon · 2011
    Not checked
  282. 282.

    Pujada A Walter L Patel A Bui TA Zhang Z Zhang Y. Matrix metalloproteinase MMP9 maintains epithelial barrier function and preserves mucosal lining in colitis associated cancer. Oncotarget (2017 ) 8(55):94650–65

    Not in our library10.18632/oncotarget.21841

  283. 283.

    Tang K Wu Z Sun M Huang X Sun J Shi J. Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice. Cancer Lett (2022 ) 529:53–69

    Not in our library10.1016/j.canlet.2021.12.033

  284. 284.

    Kim YJ Lee JS Hong KS Chung JW Kim JH Hahm KB. Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression. Cancer Prev Res (2010 ) 3(8):963–74

    Not in our library10.1158/1940-6207.capr-10-0033

  285. 285.

    Kim YJ Hong KS Chung JW Kim JH Hahm KB. Prevention of colitis-associated carcinogenesis with infliximab. Cancer Prev Res (2010 ) 3(10):1314–33

    Not in our library10.1158/1940-6207.capr-09-0272

  286. 286.

    Yoon SM Myung S-J Ye BD Kim I-W Lee NG Ryu YM. Near-infrared fluorescence imaging using a protease-specific probe for the detection of colon tumors. Gut Liver (2010 ) 4(4):488–97

    Not in our library10.5009/gnl.2010.4.4.488

  287. 287.

    Setia S Nehru B Sanyal SN. The PI3K/Akt pathway in colitis associated colon cancer and its chemoprevention with celecoxib, a Cox-2 selective inhibitor. BioMed Pharmacother (2014 ) 68(6):721–7

    Not in our library10.1016/j.biopha.2014.07.006

  288. 288.

    Yu M Trobridge P Wang Y Kanngurn S Morris SM Knoblaugh S. Inactivation of TGF-β signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene (2014 ) 33(12):1538–47

    Not in our library10.1038/onc.2013.102

  289. 289.

    Trobridge P Knoblaugh S Washington MK Munoz NM Tsuchiya KD Rojas A. TGF-β receptor inactivation and mutant kras induce intestinal neoplasms in mice via a β-catenin-independent pathway. Gastroenterology (2009 ) 136(5):1680–8.e7

    Not in our library10.1053/j.gastro.2009.01.066

  290. 290.
    Antimicrobial peptides and gut microbiota in homeostasis and pathology · 2013
    No notice
  291. 291.

    Liévin-Le Moal V Servin AL. The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: Mucins, antimicrobial peptides, and microbiota. Clin Microbiol Rev (2006 ) 19(2):315–37

    Not in our library10.1128/cmr.19.2.315-337.2006

  292. 292.

    Gallo RL Hooper LV. Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol (2012 ) 12(7):503–16

    Not in our library10.1038/nri3228

  293. 293.

    Ai F Zhang X Li X Qin Z Ye Q Tian L. Up-regulation of matrix metalloproteinases in a mouse model of chemically induced colitis-associated cancer: The role of micrornas. Oncotarget (2015 ) 6(7):5412–25

    Not in our library10.18632/oncotarget.3027

  294. 294.

    Väyrynen JP Vornanen J Tervahartiala T Sorsa T Bloigu R Salo T. Serum MMP-8 levels increase in colorectal cancer and correlate with disease course and inflammatory properties of primary tumors. Int J Cancer (2012 ) 131(4):E463–74

    Not in our library10.1002/ijc.26435

  295. 295.

    Van Lint P Libert C. Matrix metalloproteinase-8: Cleavage can be decisive. Cytokine Growth Factor Rev (2006 ) 17(4):217–23

    Not in our library10.1016/j.cytogfr.2006.04.001

  296. 296.

    Van Lint P Wielockx B Puimège L Noël A López-Otin C Libert C. Resistance of collagenase-2 (Matrix metalloproteinase-8)-Deficient mice to TNF-induced lethal hepatitis. J Immunol (2005 ) 175(11):7642–9

    Not in our library10.4049/jimmunol.175.11.7642

  297. 297.

    Tyan K Abu-Shawer O Baginska J Severgnini M Manos M Vaitkevicius H. Multiple high-grade and rare immune-related adverse events in a colon cancer patient with genomic and cytokine profiling. Immunotherapy (2022 ) 14(11):843–50

    Not in our library10.2217/imt-2021-0298

  298. 298.
    Intestinal permeability – a new target for disease prevention and therapy · 2014
    No notice
  299. 299.

    Ignacio A Morales CI Câmara NO Almeida RR. Innate sensing of the gut microbiota: Modulation of inflammatory and autoimmune diseases. Front Immunol (2016 ) 7:54

    Not in our library10.3389/fimmu.2016.00054

  300. 300.
    Chronic Inflammation and Cytokines in the Tumor Microenvironment · 2014
    No notice
  301. 301.

    West NR McCuaig S Franchini F Powrie F. Emerging cytokine networks in colorectal cancer. Nat Rev Immunol (2015 ) 15(10):615–29

    Not in our library10.1038/nri3896

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    Sirniö P Tuomisto A Tervahartiala T Sorsa T Klintrup K Karhu T. High-serum MMP-8 levels are associated with decreased survival and systemic inflammation in colorectal cancer. Br J Cancer (2018 ) 119(2):213–9

    Not in our library10.1038/s41416-018-0136-4

  303. 303.

    Mattaveewong T Wongkrasant P Chanchai S Pichyangkura R Chatsudthipong V Muanprasat C. Chitosan oligosaccharide suppresses tumor progression in a mouse model of colitis-associated colorectal cancer through AMPK activation and suppression of NF-κB and mTOR signaling. Carbohydr Polymers (2016 ) 145:30–6

    Not in our library10.1016/j.carbpol.2016.02.077

  304. 304.
    Crucial Involvement of Tumor-Associated Neutrophils in the Regulation of Chronic Colitis-Associated Carcinogenesis in Mice · 2012
    No notice
  305. 305.

    Baggiolini M. Chemokines and leukocyte traffic. Nature (1998 ) 392(6676):565–8

    Not in our library10.1038/33340

  306. 306.

    Pham CT. Neutrophil serine proteases: Specific regulators of inflammation. Nat Rev Immunol (2006 ) 6(7):541–50

    Not in our library10.1038/nri1841

  307. 307.

    Strieter RM Polverini PJ Kunkel SL Arenberg DA Burdick MD Kasper J. The functional role of the elr motif in CXC chemokine-mediated angiogenesis. J Biol Chem (1995 ) 270(45):27348–57

    Not in our library10.1074/jbc.270.45.27348

  308. 308.

    Yagi Y Andoh A Inatomi O Tsujikawa T Fujiyama Y. Inflammatory responses induced by interleukin-17 family members in human colonic subepithelial myofibroblasts. J Gastroenterol (2007 ) 42(9):746–53

    Not in our library10.1007/s00535-007-2091-3

  309. 309.

    Monteleone G Caruso R Fina D Peluso I Gioia V Stolfi C. Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut (2006 ) 55(12):1774–80

    Not in our library10.1136/gut.2006.093187

  310. 310.

    Xie Z Qu Y Leng Y Sun W Ma S Wei J. Human colon carcinogenesis is associated with increased interleukin-17-Driven inflammatory responses. Drug design Dev Ther (2015 ) 9:1679–89

    Not in our library10.2147/dddt.s79431

  311. 311.

    Hata K Andoh A Shimada M Fujino S Bamba S Araki Y. Il-17 stimulates inflammatory responses via nf-κB and MAP kinase pathways in human colonic myofibroblasts. Am J Physiol Gastrointestinal Liver Physiol (2002 ) 282(6):G1035–44

    Not in our library10.1152/ajpgi.00494.2001

  312. 312.

    Pedersen G. Development, validation and implementation of an in vitro model for the study of metabolic and immune function in normal and inflamed human colonic epithelium. Danish Med J (2015 ) 62(1):B4973.

    Not in our library

  313. 313.

    Mortensen JH Godskesen LE Jensen MD Van Haaften WT Klinge LG Olinga P. Fragments of citrullinated and MMP-degraded vimentin and MMP-degraded type iii collagen are novel serological biomarkers to differentiate Crohn's disease from ulcerative colitis. J Crohns Colitis (2015 ) 9(10):863–72

    Not in our library10.1093/ecco-jcc/jjv123

  314. 314.

    Langers AMJ Verspaget HW Hawinkels LJAC Kubben FJGM van Duijn W van der Reijden JJ. MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients. Br J Cancer (2012 ) 106(9):1495–8

    Not in our library10.1038/bjc.2012.80

  315. 315.

    Maurel J Nadal C Garcia-Albeniz X Gallego R Carcereny E Almendro V. Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients. Int J Cancer (2007 ) 121(5):1066–71

    Not in our library10.1002/ijc.22799

  316. 316.

    Martínez-Fernandez A García-Albeniz X Pineda E Visa L Gallego R Codony-Servat J. Serum matrilysin levels predict outcome in curatively resected colorectal cancer patients. Ann Surg Oncol (2009 ) 16(5):1412–20

    Not in our library10.1245/s10434-009-0405-9

  317. 317.

    Shantha Kumara HMC Gaita DJ Miyagaki H Yan X Herath SAC Cekic V. Minimally invasive colorectal resection is associated with significantly elevated levels of plasma matrix metalloproteinase 3 (MMP-3) during the first month after surgery which may promote the growth of residual metastases. Surg Endosc (2014 ) 28(12):3322–8

    Not in our library10.1007/s00464-014-3612-9

  318. 318.

    Erlichman C Adjei AA Alberts SR Sloan JA Goldberg RM Pitot HC. Phase I study of the matrix metalloproteinase inhibitor, BAY12-9566. Ann Oncol (2001 ) 12(3):389–95

    Not in our library10.1023/a:1011183905848

  319. 319.

    Heath EI O'Reilly S Humphrey R Sundaresan P Donehower RC Sartorius S. Phase I trial of the matrix metalloproteinase inhibitor BAY12-9566 in patients with advanced solid tumors. Cancer Chemother Pharmacol (2001 ) 48(4):269–74

    Not in our library10.1007/s002800100330

  320. 320.

    Rizvi NA Humphrey JS Ness EA Johnson MD Gupta E Williams K. A phase I study of oral bms-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer. Clin Cancer Res (2004 ) 10(6):1963–70

    Not in our library10.1158/1078-0432.ccr-1183-02

  321. 321.

    Mohammadzadeh M Faramarzi E Mahdavi R Nasirimotlagh B Asghari Jafarabadi M. Effect of conjugated linoleic acid supplementation on inflammatory factors and matrix metalloproteinase enzymes in rectal cancer patients undergoing chemoradiotherapy. Integr Cancer Ther (2013 ) 12(6):496–502

    Not in our library10.1177/1534735413485417

  322. 322.

    Farsad-Naeimi A Alizadeh M Esfahani A Darvish Aminabad E. Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. Food Funct (2018 ) 9(4):2025–31

    Not in our library10.1039/c7fo01898c

  323. 323.

    Levin M Udi Y Solomonov I Sagi I. Next generation matrix metalloproteinase inhibitors - novel strategies bring new prospects. Biochim Biophys Acta Mol Cell Res (2017 ) 1864(11 Pt A):1927–39

    Not in our library10.1016/j.bbamcr.2017.06.009

  324. 324.

    Zucker S Cao J Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene (2000 ) 19(56):6642–50

    Not in our library10.1038/sj.onc.1204097

  325. 325.

    Shi Y Ma X Fang G Tian X Ge C. Matrix metalloproteinase inhibitors (MMPIS) as attractive therapeutic targets: Recent progress and current challenges. NanoImpact (2021 ) 21:100293

    Not in our library10.1016/j.impact.2021.100293

  326. 326.

    Winer A Adams S Mignatti P. Matrix metalloproteinase inhibitors in cancer therapy: Turning past failures into future successes. Mol Cancer Ther (2018 ) 17(6):1147–55

    Not in our library10.1158/1535-7163.mct-17-0646

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