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The Role of the Extracellular Matrix in Cancer Stemness

Sameera Nallanthighal, James Patrick Heiserman, Dong-Joo Cheon

Frontiers in Cell and Developmental Biology · 2019 · CC BY

doi:10.3389/fcell.2019.00086

Abstract

As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called "cancer stem cells" (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction: ECM as a CSC Niche

The extracellular matrix (ECM) is a major structural component of the tumor microenvironment and comprised of a network of biochemically distinct components, including fibrous proteins, glycoproteins, proteoglycans, and polysaccharides. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or modified. Increasing evidence suggests that the ECM serves as a niche for normal and cancer stem cells (CSCs). CSCs, also called tumor-initiating cells, are a small population of cells within tumors that have capabilities of self-renewal properties, tumor initiation and chemoresistance. As one of the CSC niches, the ECM provides both structural and biochemical support to regulate proliferation, self-renewal, and differentiation of CSCs. In this review, we will cover the current understanding of how different ECM components affect the cancer “stemness” phenotype.

Fibrous ECM Proteins

Collagens constitute the main structural element of the ECM and are the most copious type of fibrous proteins within the interstitial ECM. Collagens play a role in tissue development by providing mechanical strength, altering cell adhesion, promoting cell migration. Studies have reported that several collagens (e.g., COL3A1, COL4A2, COL7A1, COL17A1) are overexpressed by CSCs (Table 1). Multiple collagen subtypes have been shown to increase epithelial-mesenchymal transition (EMT), tumor-initiating potential, drug resistance and self-renewal of CSCs (Table 1 and Figure 1).

Glycoproteins

Glycoproteins, which make the ECM a cohesive network of molecules by linking cells together with structural components, include fibulin, fibrillin, laminin, fibronectin, vitronectin, tenascin-C, Secreted Protein Acidic and Rich in Cysteine (SPARC), periostin (POSTN), thrombospondin, mucins (MUCs) and nidogen (Table 1). CSCs overexpress several glycoproteins (e.g., tenascin-C, POSTN, MUC1) and their receptors (e.g., integrins αVβ3 and α9β1, CD47). Adhesive glycoproteins bind to integrins, non-integrin receptors, growth factors, and other ECM components to activate downstream signaling pathways to regulate EMT, self-renewal, and drug resistance of CSCs (Table 1). For example, fibronectin, a major adhesive ECM glycoprotein that attaches cells to a variety of ECM components, has been shown to increase EMT, self-renewal, expression of CSC markers and drug resistance of CSCs. Laminins, another class of adhesive glycoproteins that constitute structural scaffolding of all basement membranes, support self-renewal of CSCs through their interaction with integrins. Some glycoproteins have dual roles in cancer stemness depending on the cancer type. For instance, fibulin-3, an ECM glycoprotein associated with basement membranes, inhibits self-renewal in lung and pancreatic CSCs while stimulating breast CSC self-renewal (Table 1).

Proteoglycans

Proteoglycans are glycosylated proteins composed of a core protein and one or several covalently attached sulfated glycosaminoglycan chains and are present in the ECM of connective tissues. Proteoglycans play a crucial role in ECM assembly and cell signaling. They bind to growth factors, cytokines and other ECM molecules and act as co-receptors to assist ligand and cell surface binding to modulate downstream signaling. Several proteoglycans (e.g., decorin, lumican, biglycan, versican, aggrecan) are highly expressed by CSCs and their roles in cancer stemness are summarized in Table 1.

Polysaccharides

Polysaccharides, a chain of monosaccharide repeats linked through glycosidic bonds, fill the interstitial space and buffer physical stress on the ECM. Hyaluronic acid (HA or “hyaluronan”) is a high-molecular-mass polysaccharide that constitutes a major component of interstitial gels, especially in soft connective tissues. In tumors, HA is produced by both tumor stroma and tumor cells, and its binding to the cellular receptor CD44 activates intracellular signaling (e.g., PI3K/Akt and Erk pathways, RhoA and Rac, Ras, NF-kB and Src signaling) to promote cell survival, cancer stemness, motility and invasion by cytoskeletal reorganization. High levels of HA are produced by CSCs and HA–CD44 interaction has been shown to promote acquisition of CSC characteristics and chemoresistance in breast, ovarian and head and neck CSCs (Table 1).

Physical Properties

Physical properties of the ECM such as rigidity, porosity and topography impact various anchorage-dependent CSC functions. The interstitial ECM, mainly composed of collagens, proteoglycans and hyaluronan, provides a physical barrier that hinders the transport of solutes, water and chemotherapeutic drugs. In this regard, it has been shown that cisplatin, a chemotherapeutic drug frequently used to treat various solid tumors, extensively binds to collagen fibers in tumors. Binding of chemotherapeutic drugs to the ECM prevents drug penetration into tumors, thereby increasing CSC survival. The ECM also provides sites for adhesion of CSCs in the tumor microenvironment. ECM-CSC interaction via CSC receptors such as integrins (e.g., β1, α6, β3, β4), discoidin domain receptors (DDR1, DDR2), CD44 (HA receptor) and CD47 (thrombospondin 1 receptor) enhances CSC properties. For example, CSCs bind to HA through CD44 and this increases not only the expression of stemness factors NANOG and SOX2 but also MDR1 (Multi Drug Resistance 1) expression and drug resistance in breast and ovarian CSCs. The ECM also provides anchorage and homing sites for CSCs in pre-metastatic niches, initiating metastatic colonization and organotropism of cancer cells. For instance, infiltrating breast tumor cells induce the expression of POSTN in the stroma of the secondary target organ (e.g., lung). By recruiting Wnt ligands and increasing Wnt signaling in CSCs, POSTN sustains CSC population in the secondary site and promotes metastatic colonization. Changes in the ECM topology also affects CSC self-renewal by controlling the balance between symmetric and asymmetric cell divisions. The spatial distribution of the ECM has been shown to guide the orientation of the cell division axis by controlling the location of actin polymerization at the membrane through focal adhesions and the segregation of cortical components in the interphase. The β1 sub-family of integrins also regulates stem cell self-renewal by controlling the balance between symmetric and asymmetric cell divisions. Furthermore, ECM distribution affects migration of cancer cells and immune cells. During tumor progression, wavy collagen fibers become straightened and align perpendicular to the tumor boundary. It has been shown that linear collagen fibers oriented perpendicular to the tumors facilitate high-speed migration of breast cancer cells and paired macrophages to promote metastasis to distant organs.

Mechanical Properties

Tumor ECM is typically stiffer than normal tissue ECM due to overexpression of many ECM components (e.g., collagens I, II, III, V, IX, and XI, heparan sulfate proteoglycans) and ECM-modifying enzymes [e.g., lysyl oxidase (LOX)]. Mechanical properties conferred by ECM stiffness are transmitted to CSCs through the formation of focal adhesions and subsequent activation of mechanotransduction pathways (e.g., Rho/ROCK, YAP/TAZ). ECM stiffness plays a crucial role in regulating stem cell self-renewal and differentiation. Several studies have demonstrated that ECM stiffness directs human mesenchymal stem cells (MSCs) and neural stem cells to differentiate into different cell lineages. Human MSCs cultured on hydrogel with an elastic modulus very similar to bone marrow, exhibit enhanced self-renewal and multipotency. In the case of melanoma CSCs, three-dimensional (3D) soft fibrin matrices promote histone 3 lysine residue 9 (H3K9) demethylation and increase SOX2 expression and self-renewal, whereas stiff matrices exert the opposite effects. Conversely, breast CSCs increase CSC marker expression on stiff matrix through integrin linked kinase (ILK) signaling, suggesting that the effect of matrix stiffness on stemness is cancer type specific.

EMT/De-Differentiation

The ECM can provide external cues that induce EMT, one of the cellular transformation processes that has been shown to route some cancer cell types from a differentiated to a stem cell state. Collagen I has been shown to induce EMT through activation of ILK and subsequently NF-κB-dependent inactivation of GSK-3β, along with the nuclear translocation of β-catenin. Collagen XVII and laminin-5 can also induce EMT-driven cancer stemness through the activation of FAK/Akt paired with inhibition of GSK-3β. The induction of EMT and CSC phenotypes by the ECM seems to be driven by a master regulator, Akt. Akt activation, which can be achieved via intracellular focal adhesion proteins such as FAK and ILK, subsequently modulates the activity of downstream effectors. For instance, Akt can activate NF-κB, which has been shown to upregulate the expression the stemness genes SOX2, NANOG and KLF4 in breast and prostate cancer cells. Akt, as well as ILK, can also inactivate GSK-3β, which increases the nuclear translocation of β-catenin, a transcription factor that is associated with stemness and is also an activator of NOTCH and Wnt signaling. Therefore, ECM regulates the switch between CSC and non-CSC states by inducing EMT.

Self-Renewal/Maintenance

The ECM also promotes CSC self-renewal. In this regard, collagen I has been shown to preserve stemness in malignant and non-malignant stem cells by activating transcriptional programs that induce self-renewal. Binding of collagen to α2β1 integrin results in the nuclear translocation of Bmi1, a stemness-inducing transcription factor downstream of Hedgehog signaling. Studies have shown that Bmi1 is a transcriptional target of Gli1, a stemness related gene, and that FAK/Ras signaling enhances the expression of Gli1. Akt/p-S6K1 signaling has also been shown to play a regulatory role in activity of Gli1. Laminin and fibronectin signaling also plays a crucial role in CSC self-renewal. Laminin 511 can sustain breast cancer stemness through activation of α6β1 integrin, in a TAZ-dependent manner. TAZ expression and nuclear localization induce the expression of the stemness transcription factors, OCT4, SOX2 and NANOG in non-malignant and malignant cells. Fibronectin’s extra domain A (EDA) has also been demonstrated to positively regulate CSC self-renewal through activation of α9β1 integrin/FAK/ERK/Akt/β-catenin pathway.

Growth Factor Reservoir and Release

The ECM might serve as a reservoir for factors that aid in the sustenance of CSCs. Embryonic stem cells (ESCs) have been shown to utilize matrix metalloproteases 1 (MMP1) to release ciliary neurotropic factor (CNTF) from an ESC-derived matrix, which enhances ESC self-renewal though JAK/STAT3 signaling, a pathway that has also been implicated in promoting self-renewal of breast CSCs. Hematopoietic stem cells (HSCs) also upregulate MMP-9 to release soluble kit-ligand, also known as stem cell factor (SCF), which promotes survival signaling and chemoresistance in many types of cancers. CSCs are thought to remodel their matrices more significantly than their non-cancer stem cell counterparts as CSCs upregulate expression of different MMPs. This may enable them to effectively degrade and remodel ECM matrices to release growth factors and cytokines to promote their survival.

Metabolic Reprogramming and Autophagy

The ECM serves as a functional repository for a plethora of factors that dynamically modulate the tumor microenvironment to promote CSC metabolism. Focal adhesion formations transduce ECM signaling into the tumor cells and activate the PI3K pathway which increases glycolysis, in addition to activating glutamine signaling in a Ras- and Myc- dependent manner. Furthermore, a stiff ECM acts as a driver of glycolysis in CSCs. On the contrary, accumulating evidence suggests that CSCs also utilize OXPHOS, fatty acid oxidation and glutaminolysis. In this regard, it has been demonstrated that CSCs with high telomerase activity upregulate glycolysis and OXPHOS in lung and ovarian cancers. Given the diversity of tumors and their microenvironments, it is possible that based on the availability of nutrients, CSCs can manipulate their metabolism. For example, while CSCs in a hypoxic microenvironment may survive by means of glycolysis, CSCs in a normoxic environment use oxidative metabolism. Furthermore, CSCs utilize metabolites secreted by cancer-associated fibroblasts such as lactate and ketone bodies to fuel OXPHOS. Recycling of nutrients via autophagy is another way by which CSCs not only self-renew but also acquire drug resistance. Autophagy impairment downregulates the expression of CSC markers and consequently the CSC self-renewal capacity in breast, liver, ovarian and pancreatic cancers, osteosarcoma and gliobastoma. ECM-receptor ligation has been shown to induce autophagy. Collagen VI, a promoter of tumorigenesis and a supporter of stem cell niches, also functions as an autophagy inducer in skeletal muscle stem cells by functionally interacting with decorin, a small leucin-rich proteoglycans (SLRP) that has been shown to induce stemness in glioblastoma. A growing number of studies indicate that collagen VI directly maintains CSCs by activating the Akt–GSK-3β–β-catenin–TCF/LEF axis, which is required for activation of autophagy. Decorin signaling, independent of Collagen VI, can also maintain stemness of trophoblasts and prevent their differentiation.

Role of Hypoxia in ECM-Derived Cancer Stemness

Solid tumors frequently contain highly hypoxic regions and tumor hypoxia is positively associated with poor prognosis. Hypoxic tumor cells express stem cell markers, are highly undifferentiated and exhibit enhanced clonogenic potential in vitro and tumor initiating potential in vivo. Furthermore, hypoxia can lead to increased ECM deposition and remodeling. Histological studies on clinical tumor samples have shown increased collagen deposition resulting in fibrosis in hypoxic regions of tumors. In addition to cancer cells, fibroblasts cultured under hypoxic conditions show increased type I procollagen α1 mRNA. Abrogating HIF1α expression inhibits collagen deposition from both breast cancer cells and fibroblasts in vitro and in vivo. ECM remodeling enzymes such as LOX, LOX-like protein 2 (LOXL2), LOXL4, MMP2, MMP9 and MMP14 and growth factors inducing collagen deposition (e.g., VEGF) are HIF-regulated genes that are involved in tumor fibrosis. Since all these factors have been previously implicated cancer stemness, it is not surprising that the ECM acts a functional conduit for hypoxia-derived signals that foster cancer stemness.

ECM Modulates Immune Surveillance in CSC Microenvironment

Extracellular matrix can profoundly influence recruitment of immune cells into the tumor microenvironment. CSCs can evade immune surveillance by altering this microenvironment to favor their survival. For example, ECM drives the activation of pro-survival pathways such as PI3K/AKT, which has been shown to facilitate immune evasion in CSCs. ECM proteins can recruit immunosuppressive cells such as tumor-associated macrophages (TAMs) and regulatory T cells that have been known to promote CSC survival, while simultaneously blocking the recruitment of antitumorigenic immune cells such as cytotoxic T cells. In addition, the ECM composition can dramatically modulate the activation state of the tumor infiltrating immune cells. For instance, a stiff collagen-rich or POSTN-rich ECM allows macrophage polarization to a pro-tumorigenic M2 phenotype. Following recruitment, the M2 macrophages activate several CSC survival signaling pathways including Src, NF-κB, STAT3/SOX2 and Hedgehog. ECM can also impair proliferation and activation of T cells, that are required for capturing and killing CSCs. A collagen-rich ECM can inhibit T-cell proliferation and activation through type I collagen-dependent fusion of LAIR receptors in addition to sequestering growth factors required for T cell proliferation. Furthermore, TAMs and neutrophils that can selectively reorganize the ECM to promote malignant growth of cancers are preferentially recruited to the microenvironment.

CSC Targeting Therapies

Currently, there are several inhibitors targeting various aspects of ECM-induced cancer stemness that are undergoing clinical testing. For example, the CD47 blocking protein TTI-621 is currently being assessed in a number of phase I clinical trials (NCT03013218, NCT02663518, NCT02216409, NCT02678338) for various types of cancers. Other groups have targeted FAK with the inhibitor VS-6063 (Defactinib), which has completed clinical phase I and II trials (NCT01778803, NCT01943292, NCT01951690) with one of those clinical trials assessing for CSCs as an endpoint (NCT01778803). Other inhibitors of stemness-related molecules further downstream of ECM signaling are also being tested in clinical trials, such as the STAT3 inhibitor BBI-608 in a phase II trial that will test for presence of CSC as an endpoint (NCT02279719) and in a phase III clinical trial aimed at reducing CSCs by targeting phosphorylated Stat3 positive cancer cells (NCT02753127). The β-catenin pathway inhibitors PRI-724 and CWP232291 are currently being tested in two phase I clinical trials (NCT01764477, NCT01398462). Inhibition of the Hedgehog pathway with the inhibitor GDC-0449 (Vismodegib), is also currently being clinically evaluated in a phase II trial which will test for the presence of pancreatic CSCs (NCT01088815).

Challenges and Conclusion

Although the above drugs may effectively reduce the number of CSCs, there are still many potential challenges that ECM components in a tumor microenvironment may set that could interfere with an otherwise successful treatment regimen. Firstly, ECM proteins have been shown to act as a physical barrier, making drug delivery to cancer cells more difficult. Secondly, ECM proteins can de-differentiate non-CSCs into CSCs, which makes eliminating all CSCs more challenging. Thirdly, ECM plays a role in modulating immune cell recruitment, hence, potential immunotherapeutic strategies could be hindered by dysregulated ECM components. Finally, the ECM has a very complex and dynamic nature: different ECM molecules are expressed in a time and tissue-specific manner where various isoforms of the same molecule can play opposing functions in cancer stemness in a context-dependent manner. Considering these concerns, it is crucial that future studies further elucidate the role of ECM components on cancer stemness in order to design therapies that effectively eradicate all CSCs.

Author Contributions

All authors conceptualized the content and wrote the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Ichii M. Frank M. B. Iozzo R. V. Kincade P. W. (2012 ). The canonical Wnt pathway shapes niches supportive of hematopoietic stem/progenitor cells. Blood 119 1683–1692.

    Not in our library10.1182/blood-2011-07-369199

  44. 44.

    Inoue A. Takahashi H. Harada H. Kohno S. Ohue S. Kobayashi K. (2010 ). Cancer stem-like cells of glioblastoma characteristically express MMP-13 and display highly invasive activity. Int. J. Oncol. 371121–1131.

    Not in our library10.3892/ijo_00000764

  45. 45.

    Jaiswal S. Jamieson C. H. M. Pang W. W. Park C. Y. Chao M. P. Majeti R. (2009 ). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138 271–285.

    Not in our library10.1016/j.cell.2009.05.046

  46. 46.

    Januchowski R. Swierczewska M. Sterzynska K. Wojtowicz K. Nowicki M. Zabel M. (2016 ). Increased expression of several collagen genes is associated with drug resistance in ovarian cancer cell lines. J. Cancer 7 1295–1310.

    Not in our library10.7150/jca.15371

  47. 47.

    Jinushi M. Chiba S. Yoshiyama H. Masutomi K. Kinoshita I. Dosaka-Akita H. (2011 ). Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc. Natl. Acad. Sci. U.S.A. 108 12425–12430.

    Not in our library10.1073/pnas.1106645108

  48. 48.

    Jogi A. Ora I. Nilsson H. Lindeheim A. Makino Y. Poellinger L. (2002 ). Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc. Natl. Acad. Sci. U.S.A. 99 7021–7026.

    Not in our library10.1073/pnas.102660199

  49. 49.

    Kabos P. Matundan H. Zandian M. Bertolotto C. Robinson M. L. Davy B. E. (2004 ). Neural precursors express multiple chondroitin sulfate proteoglycans, including the lectican family. Biochem. Biophys. Res. Commun. 318 955–963.

    Not in our library10.1016/j.bbrc.2004.04.114

  50. 50.

    Kato M. Saunders S. Nguyen H. Bernfield M. (1995 ). Loss of cell-surface syndecan-1 causes epithelia to transform into anchorage-independent mesenchyme-like cells. Mol. Biol. Cell 6 559–576.

    Not in our library10.1091/mbc.6.5.559

  51. 51.

    Kaur S. Elkahloun A. G. Singh S. P. Chen Q. R. Meerzaman D. M. Song T. (2016 ). A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triple-negative breast cancer. Oncotarget 7 10133–10152.

    Not in our library10.18632/oncotarget.7100

  52. 52.

    Kaur S. Soto-Pantoja D. R. Stein E. V. Liu C. Y. Elkahloun A. G. Pendrak M. L. (2013 ). Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors. Sci. Rep. 3:1673.

    Not in our library10.1038/srep01673

  53. 53.

    Kawano S. Torisu T. Esaki M. Torisu K. Matsuno Y. Kitazono T. (2017 ). Autophagy promotes degradation of internalized collagen and regulates distribution of focal adhesions to suppress cell adhesion. Biol. Open 6 1644–1653.

    Not in our library10.1242/bio.027458

  54. 54.

    Kim I. G. Kim S. Y. Choi S. I. Lee J. H. Kim K. C. Cho E. W. (2014a ). Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling. Oncogene 33 3908–3917.

    Not in our library10.1038/onc.2013.373

  55. 55.

    Kim I. G. Lee J. H. Kim S. Y. Kim J. Y. Cho E. W. (2014b ). Fibulin-3 negatively regulates ALDH1 via c-MET suppression and increases gamma-radiation-induced sensitivity in some pancreatic cancer cell lines. Biochem. Biophys. Res. Commun. 454 369–375.

    Not in our library10.1016/j.bbrc.2014.10.084

  56. 56.

    Kim H. P. Han S. W. Song S. H. Jeong E. G. Lee M. Y. Hwang D. (2014c ). Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer. Oncogene 33 3334–3341.

    Not in our library10.1038/onc.2013.285

  57. 57.

    Kim Y. Lin Q. Zelterman D. Yun Z. (2009 ). Hypoxia-regulated delta-like 1 homologue enhances cancer cell stemness and tumorigenicity. Cancer Res. 69 9271–9280.

    Not in our library10.1158/0008-5472.can-09-1605

  58. 58.

    Kirkland S. C. (2009 ). Type I collagen inhibits differentiation and promotes a stem cell-like phenotype in human colorectal carcinoma cells. Br. J. Cancer 101 320–326.

    Not in our library10.1038/sj.bjc.6605143

  59. 59.

    Kreso A. Dick J. E. (2014 ). Evolution of the cancer stem cell model. Cell Stem Cell 14 275–291.

    Not in our library10.1016/j.stem.2014.02.006

  60. 60.

    Kwak J. H. Lee N. H. Lee H. Y. Hong I. S. Nam J. S. (2016 ). HIF2alpha/EFEMP1 cascade mediates hypoxic effects on breast cancer stem cell hierarchy. Oncotarget 7 43518–43533.

    Not in our library10.18632/oncotarget.9846

  61. 61.

    Lambert A. W. Wong C. K. Ozturk S. Papageorgis P. Raghunathan R. Alekseyev Y. (2016 ). Tumor cell-derived periostin regulates cytokines that maintain breast cancer stem cells. Mol. Cancer Res. 14 103–113.

    Not in our library10.1158/1541-7786.mcr-15-0079

  62. 62.

    Laperle A. Hsiao C. Lampe M. Mortier J. Saha K. Palecek S. P. (2015 ). alpha-5 laminin synthesized by human pluripotent stem cells promotes self-renewal. Stem Cell Rep. 5 195–206.

    Not in our library10.1016/j.stemcr.2015.06.009

  63. 63.

    Lathia J. D. Li M. Hall P. E. Gallagher J. Hale J. S. Wu Q. (2012 ). Laminin alpha 2 enables glioblastoma stem cell growth. Ann. Neurol. 72 766–778.

    Not in our library10.1002/ana.23674

  64. 64.

    Lechler T. Fuchs E. (2005 ). Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437 275–280.

    Not in our library10.1038/nature03922

  65. 65.

    Levental K. R. Yu H. Kass L. Lakins J. N. Egeblad M. Erler J. T. (2009 ). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139 891–906.

    Not in our library10.1016/j.cell.2009.10.027

  66. 66.

    Li A. Zhou T. Guo L. Si J. (2010 ). Collagen type I regulates beta-catenin tyrosine phosphorylation and nuclear translocation to promote migration and proliferation of gastric carcinoma cells. Oncol. Rep. 23 1247–1255.

    Not in our library10.3892/or_00000757

  67. 67.

    Li C. L. Yang D. Cao X. Wang F. Hong D. Y. Wang J. (2017 ). Fibronectin induces epithelial-mesenchymal transition in human breast cancer MCF-7 cells via activation of calpain. Oncol. Lett. 13 3889–3895.

    Not in our library10.3892/ol.2017.5896

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    Lim Y. C. Oh S. Y. Kim H. (2012 ). Cellular characteristics of head and neck cancer stem cells in type IV collagen-coated adherent cultures. Exp. Cell Res. 318 1104–1111.

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    Lin H. M. Lee B. Y. Castillo L. Spielman C. Grogan J. Yeung N. K. (2018 ). Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer. Prostate 78 308–317.

    Not in our library10.1002/pros.23476

  70. 70.

    Liu B. Xu T. Xu X. Cui Y. Xing X. (2018 ). Biglycan promotes the chemotherapy resistance of colon cancer by activating NF-kappaB signal transduction. Mol. Cell. Biochem. 449 285–294.

    Not in our library10.1007/s11010-018-3365-1

  71. 71.

    Liu C. C. Lin J. H. Hsu T. W. Hsu J. W. Chang J. W. Su K. (2016 ). Collagen XVII/laminin-5 activates epithelial-to-mesenchymal transition and is associated with poor prognosis in lung cancer. Oncotarget 9 1656–1672.

    Not in our library10.18632/oncotarget.11208

  72. 72.

    Liu J. Tan Y. Zhang H. Zhang Y. Xu P. Chen J. (2012 ). Soft fibrin gels promote selection and growth of tumorigenic cells. Nat. Mater. 11 734–741.

    Not in our library10.1038/nmat3361

  73. 73.

    Liu M. Sakamaki T. Casimiro M. C. Willmarth N. E. Quong A. A. Ju X. (2010 ). The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 70 10464–10473.

    Not in our library10.1158/0008-5472.can-10-0732

  74. 74.

    Long H. Xie R. Xiang T. Zhao Z. Lin S. Liang Z. (2012 ). Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-kappaB-mediated MMP-9 upregulation. Stem Cells 30 2309–2319.

    Not in our library10.1002/stem.1194

  75. 75.

    Lu H. H. Clauser K. R. Tam W. L. Frose J. Ye X. Eaton E. N. (2014 ). A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 16 1105–1117.

    Not in our library10.1038/ncb3041

  76. 76.

    Lu P. Weaver V. M. Werb Z. (2012 ). The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196 395–406.

    Not in our library10.1083/jcb.201102147

  77. 77.

    Majeti R. Chao M. P. Alizadeh A. A. Pang W. W. Jaiswal S. Gibbs K. D. (2009 ). CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138 286–299.

    Not in our library10.1016/j.cell.2009.05.045

  78. 78.

    Malanchi I. Santamaria-Martínez A. Susanto E. Peng H. Lehr H. A. Delaloye J. F. (2011 ). Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481 85–89.

    Not in our library10.1038/nature10694

  79. 79.

    Mani S. A. Guo W. Liao M. J. Eaton E. N. Ayyanan A. Zhou A. Y. (2008 ). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133 704–715.

    Not in our library10.1016/j.cell.2008.03.027

  80. 80.
    Asporin Is a Fibroblast-Derived TGF-β1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer. · 2015
    Not checked
  81. 81.

    Martinez F. O. Gordon S. (2014 ). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13.

    Not in our library10.12703/p6-13

  82. 82.

    Martinez-Outschoorn U. E. Peiris-Pages M. Pestell R. G. Sotgia F. Lisanti M. P. (2017 ). Cancer metabolism: a therapeutic perspective. Nat. Rev. Clin. Oncol. 14:113.

    Not in our library10.1038/nrclinonc.2017.1

  83. 83.

    Mateo F. Meca-Cortes O. Celia-Terrassa T. Fernandez Y. Abasolo I. Sanchez-Cid L. (2014 ). SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations. Mol. Cancer 13:237.

    Not in our library10.1186/1476-4598-13-237

  84. 84.

    Medici D. Nawshad A. (2010 ). Type I collagen promotes epithelial-mesenchymal transition through ILK-dependent activation of NF-kappaB and LEF-1. Matrix Biol. 29 161–165.

    Not in our library10.1016/j.matbio.2009.12.003

  85. 85.

    Meyaard L. (2008 ). The inhibitory collagen receptor LAIR-1 (CD305). J. Leukoc. Biol. 83 799–803.

    Not in our library10.1189/jlb.0907609

  86. 86.

    Mikheev A. M. Mikheeva S. A. Trister A. D. Tokita M. J. Emerson S. N. Parada C. A. (2015 ). Periostin is a novel therapeutic target that predicts and regulates glioma malignancy. Neuro Oncol. 17 372–382.

    Not in our library10.1093/neuonc/nou161

  87. 87.

    Mimeault M. Johansson S. L. Senapati S. Momi N. Chakraborty S. Batra S. K. (2010 ). MUC4 down-regulation reverses chemoresistance of pancreatic cancer stem/progenitor cells and their progenies. Cancer Lett. 295 69–84.

    Not in our library10.1016/j.canlet.2010.02.015

  88. 88.

    Moreira D. Zhang Q. Hossain D. M. Nechaev S. Li H. Kowolik C. M. (2015 ). TLR9 signaling through NF-kappaB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells. Oncotarget 6 17302–17313.

    Not in our library10.18632/oncotarget.4029

  89. 89.

    Motegi H. Kamoshima Y. Terasaka S. Kobayashi H. Houkin K. (2014 ). Type 1 collagen as a potential niche component for CD133-positive glioblastoma cells. Neuropathology 34 378–385.

    Not in our library10.1111/neup.12117

  90. 90.

    Mowers E. E. Sharifi M. N. Macleod K. F. (2018 ). Functions of autophagy in the tumor microenvironment and cancer metastasis. FEBS J. 285 1751–1766.

    Not in our library10.1111/febs.14388

  91. 91.

    Nandi P. Lim H. Torres-Garcia E. J. Lala P. K. (2018 ). Human trophoblast stem cell self-renewal and differentiation: role of decorin. Sci. Rep. 8:8977.

    Not in our library10.1038/s41598-018-27119-4

  92. 92.
    Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications · 2019
    No notice
  93. 93.

    Neill T. Schaefer L. Iozzo R. V. (2014 ). Instructive roles of extracellular matrix on autophagy. Am. J. Pathol. 184 2146–2153.

    Not in our library10.1016/j.ajpath.2014.05.010

  94. 94.

    Nie S. Gurrea M. Zhu J. H. Thakolwiboon S. Heth J. A. Muraszko K. M. (2015 ). Tenascin-C: a novel candidate marker for cancer stem cells in glioblastoma identified by tissue microarrays. J. Proteome Res. 14 814–822.

    Not in our library10.1021/pr5008653

  95. 95.

    Norman J. T. Clark I. M. Garcia P. L. (2000 ). Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 58 2351–2366.

    Not in our library10.1046/j.1523-1755.2000.00419.x

  96. 96.

    O’Connor R. S. Hao X. L. Shen K. Y. Bashour K. Akimova T. Hancock W. W. (2012 ). Substrate rigidity regulates human t cell activation and proliferation. J. Immunol. 189 1330–1339.

    Not in our library10.4049/jimmunol.1102757

  97. 97.

    Oktem G. Bilir A. Uslu R. Inan S. V. Demiray S. B. Atmaca H. (2014a ). Expression profiling of stem cell signaling alters with spheroid formation in CD133(high)/CD44(high) prostate cancer stem cells. Oncol. Lett. 7 2103–2109.

    Not in our library10.3892/ol.2014.1992

  98. 98.

    Oktem G. Sercan O. Guven U. Uslu R. Uysal A. Goksel G. (2014b ). Cancer stem cell differentiation: TGF beta 1 and versican may trigger molecules for the organization of tumor spheroids. Oncol. Rep. 32 641–649.

    Not in our library10.3892/or.2014.3252

  99. 99.

    Okuda H. Kobayashi A. Xia B. Watabe M. Pai S. K. Hirota S. (2012 ). Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res. 72 537–547.

    Not in our library10.1158/0008-5472.can-11-1678

  100. 100.

    Oskarsson T. Acharyya S. Zhang X. H. F. Vanharanta S. Tavazoie S. F. Morris P. G. (2011 ). Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17 867–874.

    Not in our library10.1038/nm.2379

  101. 101.

    Ou J. J. Deng J. Wei X. Xie G. F. Zhou R. B. Yu L. Q. (2013 ). Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells. Stem Cell Res. 11 820–833.

    Not in our library10.1016/j.scr.2013.05.009

  102. 102.

    Pang M. F. Siedlik M. J. Han S. Stallings-Mann M. Radisky D. C. Nelson C. M. (2016 ). Tissue stiffness and hypoxia modulate the integrin-linked kinase ilk to control breast cancer stem-like cells. Cancer Res. 76 5277–5287.

    Not in our library10.1158/0008-5472.can-16-0579

  103. 103.

    Petrova P. S. Viller N. N. Wong M. Pang X. Lin G. H. Dodge K. (2017 ). TTI-621 (SIRPalphaFc): a CD47-blocking innate immune checkpoint inhibitor with broad antitumor activity and minimal erythrocyte binding. Clin. Cancer Res 23 1068–1079.

    Not in our library10.1158/1078-0432.ccr-16-1700

  104. 104.

    Pezzolo A. Parodi F. Marimpietri D. Raffaghello L. Cocco C. Pistorio A. (2011 ). Oct-4(+)/Tenascin C+ neuroblastoma cells serve as progenitors of tumor-derived endothelial cells. Cell Res. 21 1470–1486.

    Not in our library10.1038/cr.2011.38

  105. 105.

    Pickup M. W. Mouw J. K. Weaver V. M. (2014 ). The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15 1243–1253.

    Not in our library10.15252/embr.201439246

  106. 106.

    Ponnusamy M. P. Seshacharyulu P. Vaz A. Dey P. Batra S. K. (2011 ). MUC4 stabilizes HER2 expression and maintains the cancer stem cell population in ovarian cancer cells. J. Ovarian Res. 4:7.

    Not in our library10.1186/1757-2215-4-7

  107. 107.
    Collagen reorganization at the tumor-stromal interface facilitates local invasion · 2006
    No notice
  108. 108.

    Przybyla L. M. Theunissen T. W. Jaenisch R. Voldman J. (2013 ). Matrix remodeling maintains embryonic stem cell self-renewal by activating Stat3. Stem Cells 31 1097–1106.

    Not in our library10.1002/stem.1360

  109. 109.

    Pupa S. M. Giuffre S. Castiglioni F. Bertola L. Cantu M. Bongarzone I. (2007 ). Regulation of breast cancer response to chemotherapy by fibulin-1. Cancer Res. 67 4271–4277.

    Not in our library10.1158/0008-5472.can-06-4162

  110. 110.

    Rada M. Nallanthighal S. Cha J. Ryan K. Sage J. Eldred C. (2018 ). Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer. Oncogene 37 4809–4820.

    Not in our library10.1038/s41388-018-0297-x

  111. 111.

    Raja A. M. Xu S. Zhuo S. Tai D. C. Sun W. So P. T. (2015 ). Differential remodeling of extracellular matrices by breast cancer initiating cells. J. Biophotonics 8 804–815.

    Not in our library10.1002/jbio.201400079

  112. 112.

    Reed C. C. Waterhouse A. Kirby S. Kay P. Owens R. T. McQuillan D. J. (2005 ). Decorin prevents metastatic spreading of breast cancer. Oncogene 24 1104–1110.

    Not in our library10.1038/sj.onc.1208329

  113. 113.

    Roussos E. T. Condeelis J. S. Patsialou A. (2011 ). Chemotaxis in cancer. Nat. Rev. Cancer 11 573–587.

    Not in our library10.1038/nrc3078

  114. 114.

    Saha K. Keung A. J. Irwin E. F. Li Y. Little L. Schaffer D. V. (2008 ). Substrate modulus directs neural stem cell behavior. Biophys. J. 95 4426–4438.

    Not in our library10.1529/biophysj.108.132217

  115. 115.

    Sancho P. Barneda D. Heeschen C. (2016 ). Hallmarks of cancer stem cell metabolism. Br. J. Cancer 114 1305–1312.

    Not in our library10.1038/bjc.2016.152

  116. 116.

    Sarkar S. Mirzaei R. Zemp F. J. Wei W. Senger D. L. Robbins S. M. (2017 ). Activation of notch signaling by tenascin-C promotes growth of human brain tumor-initiating cells. Cancer Res. 77 3231–3243.

    Not in our library10.1158/0008-5472.can-16-2171

  117. 117.

    Sharma S. Xing F. Liu Y. Wu K. R. Said N. Pochampally R. (2016 ). Secreted protein acidic and rich in cysteine (SPARC) mediates metastatic dormancy of prostate cancer in bone. J. Biol. Chem. 291 19351–19363.

    Not in our library10.1074/jbc.m116.737379

  118. 118.

    Shekhar M. P. Pauley R. Heppner G. (2003 ). Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 5 130–135.

    Not in our library10.1186/bcr580

  119. 119.

    Shiina M. Bourguignon L. Y. (2015 ). Selective activation of cancer stem cells by size-specific hyaluronan in head and neck cancer. Int. J. Cell Biol. 2015:989070.

    Not in our library10.1155/2015/989070

  120. 120.

    Shintani K. Matsumine A. Kusuzaki K. Morikawa J. Matsubara T. Wakabayashi T. (2008 ). Decorin suppresses lung metastases of murine osteosarcoma. Oncol. Rep. 19 1533–1539.

    Not in our library

  121. 121.

    Smaldone S. Bigarella C. L. Del Solar M. Ghaffari S. Ramirez F. (2016a ). Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis. Matrix Biol. 5 88–94.

    Not in our library10.1016/j.matbio.2015.11.006

  122. 122.

    Smaldone S. Clayton N. P. del Solar M. Pascual G. Cheng S. H. Wentworth B. M. (2016b ). Fibrillin-1 regulates skeletal stem cell differentiation by modulating TGFbeta activity within the marrow niche. J. Bone. Miner. Res. 31 86–97.

    Not in our library10.1002/jbmr.2598

  123. 123.

    Sonbol M. B. Ahn D. H. Bekaii-Saab T. (2019 ). Therapeutic targeting strategies of cancer stem cells in gastrointestinal malignancies. Biomedicines 7:17.

    Not in our library10.3390/biomedicines7010017

  124. 124.

    Soteriou D. Iskender B. Byron A. Humphries J. D. Borg-Bartolo S. Haddock M. C. (2013 ). Comparative proteomic analysis of supportive and unsupportive extracellular matrix substrates for human embryonic stem cell maintenance. J. Biol. Chem. 288 18716–18731.

    Not in our library10.1074/jbc.m113.463372

  125. 125.

    Stahl M. Schupp J. Jager B. Schmid M. Zissel G. Muller-Quernheim J. (2013 ). Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation. PLoS One 8:e81382.

    Not in our library10.1371/journal.pone.0081382

  126. 126.

    Stock C. Jungmann O. Seidler D. G. (2011 ). Decorin and chondroitin-6 sulfate inhibit B16V melanoma cell migration and invasion by cellular acidification. J. Cell. Physiol. 226 2641–2650.

    Not in our library10.1002/jcp.22612

  127. 127.

    Stroopinsky D. Rosenblatt J. Ito K. Mills H. Yin L. Rajabi H. (2013 ). MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Res. 73 5569–5579.

    Not in our library10.1158/0008-5472.can-13-0677

  128. 128.

    Suh H. N. Han H. J. (2011 ). Collagen I regulates the self-renewal of mouse embryonic stem cells through alpha 2 beta 1 integrin- and DDR1-dependent Bmi-1. J. Cell. Physiol. 226 3422–3432.

    Not in our library10.1002/jcp.22697

  129. 129.

    Sun B. Huang Z. Wang B. Yu Y. Lin S. Luo L. (2017 ). Significance of glypican-3 (GPC3) expression in hepatocellular cancer diagnosis. Med. Sci. Monit. 23 850–855.

    Not in our library10.12659/msm.899198

  130. 130.

    Sun Y. Kim H. S. Saw P. E. Jon S. Moon W. K. (2015 ). Targeted therapy for breast cancer stem cells by liposomal delivery of siRNA against fibronectin EDB. Adv. Healthc. Mater. 4 1675–1680.

    Not in our library10.1002/adhm.201500190

  131. 131.

    Taddei I. Deugnier M. A. Faraldo M. M. Petit V. Bouvard D. Medina D. (2008 ). Beta1 integrin deletion from the basal compartment of the mammary epithelium affects stem cells. Nat. Cell Biol. 10 716–722.

    Not in our library10.1038/ncb1734

  132. 132.

    Tai D. Wells K. Arcaroli J. Vanderbilt C. Aisner D. L. Messersmith W. A. (2015 ). Targeting the WNT signaling pathway in cancer therapeutics. Oncologist 20 1189–1198.

    Not in our library10.1634/theoncologist.2015-0057

  133. 133.

    Tamamori M. Ito H. Hiroe M. Marumo F. Hata R. I. (1997 ). Stimulation of collagen synthesis in rat cardiac fibroblasts by exposure to hypoxic culture conditions and suppression of the effect by natriuretic peptides. Cell Biol. Int. 21 175–180.

    Not in our library10.1006/cbir.1997.0130

  134. 134.

    Tan Y. Tajik A. Chen J. Jia Q. Chowdhury F. Wang L. (2014 ). Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression. Nat. Commun. 5:4619.

    Not in our library10.1038/ncomms5619

  135. 135.

    Thery M. Racine V. Pepin A. Piel M. Chen Y. Sibarita J. B. (2005 ). The extracellular matrix guides the orientation of the cell division axis. Nat. Cell Biol. 7 947–953.

    Not in our library10.1038/ncb1307

  136. 136.

    Urciuolo A. Quarta M. Morbidoni V. Gattazzo F. Molon S. Grumati P. (2013 ). Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4:1964.

    Not in our library10.1038/ncomms2964

  137. 137.

    Vadlamudi U. Espinoza H. M. Ganga M. Martin D. M. Liu X. Engelhardt J. F. (2005 ). PITX2, beta-catenin and LEF-1 interact to synergistically regulate the LEF-1 promoter. J. Cell Sci. 118 1129–1137.

    Not in our library10.1242/jcs.01706

  138. 138.

    Varelas X. Sakuma R. Samavarchi-Tehrani P. Peerani R. Rao B. M. Dembowy J. (2008 ). TAZ controls smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol. 10 837–848.

    Not in our library10.1038/ncb1748

  139. 139.

    Vesuna F. Lisok A. Kimble B. Raman V. (2009 ). Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia 11 1318–1328.

    Not in our library10.1593/neo.91084

  140. 140.

    Wang T. Fahrmann J. F. Lee H. Li Y.-J. Tripathi S. C. Yue C. (2018 ). JAK/STAT3-Regulated fatty Acid β-Oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 27 136.e5–150.e5.

    Not in our library10.1016/j.cmet.2017.11.001

  141. 141.

    Wang X. Zuo D. Chen Y. Li W. Liu R. He Y. (2014 ). Shed Syndecan-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer. Br. J. Cancer 111 1965–1976.

    Not in our library10.1038/bjc.2014.493

  142. 142.
    Periostin contributes to the acquisition of multipotent stem cell-like properties in human mammary epithelial cells and breast cancer cells. · 2013
    Not checked
  143. 143.

    Wang Y. Xia W. Y. Lang J. Y. Hsu J. Wang H. M. Ajani J. (2012 ). The crosstalk of mTOR/S6K1 and hedgehog pathways. Cancer Res. 72 374–387. 22439934

    Not in our library10.1158/1538-7445.am2012-989

  144. 144.

    Wesley R. B. Meng X. P. Godin D. Galis Z. S. (1998 ). Extracellular matrix modulates macrophage functions characteristic to atheroma - collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler. Thromb. Vasc. Biol. 18 432–440.

    Not in our library10.1161/01.atv.18.3.432

  145. 145.

    Winer J. P. Janmey P. A. McCormick M. E. Funaki M. (2009 ). Bone marrow-derived human mesenchymal stem cells become quiescent on soft substrates but remain responsive to chemical or mechanical stimuli. Tissue Eng. Part A 15 147–154.

    Not in our library10.1089/ten.tea.2007.0388

  146. 146.

    Wu Y. H. Chang T. H. Huang Y. F. Chen C. C. Chou C. Y. (2015 ). COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization. Oncotarget 6 23748–23763.

    Not in our library10.18632/oncotarget.4250

  147. 147.

    Wu Y. H. Huang Y. F. Chang T. H. Chou C. Y. (2017 ). Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF-kappaB-mediated IKKbeta expression. Int. J. Cancer 141 2305–2317.

    Not in our library10.1002/ijc.30932

  148. 148.

    Xiao H. Jiang N. Zhou B. Y. Liu Q. Du C. Y. (2015 ). TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma. Cancer Sci. 106 151–159.

    Not in our library10.1111/cas.12587

  149. 149.
    Prolyl-4-hydroxylase α subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition · 2014
    No notice
  150. 150.

    Yakubenko V. P. Cui K. Ardell C. L. Brown K. E. West X. Z. Gao D. (2018 ). Oxidative modifications of extracellular matrix promote the second wave of inflammation via beta2 integrins. Blood 132 78–88.

    Not in our library10.1182/blood-2017-10-810176

  151. 151.

    Yang J. Liao D. B. Chen C. Liu Y. Chuang T. H. Xiang R. (2013 ). Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells 31 248–258.

    Not in our library10.1002/stem.1281

  152. 152.

    You Y. Zheng Q. Dong Y. Xie X. Wang Y. Wu S. (2016 ). Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells. Oncotarget 7 32221–32231.

    Not in our library10.18632/oncotarget.8515

  153. 153.

    Yu Q. Xue Y. Liu J. Xi Z. Li Z. Liu Y. (2018 ). Fibronectin promotes the malignancy of glioma stem-like cells via modulation of cell adhesion. differentiation, proliferation and chemoresistance. Front. Mol. Neurosci. 11:130.

    Not in our library10.3389/fnmol.2018.00130

  154. 154.

    Yusuf N. Inagaki T. Kusunoki S. Okabe H. Yamada I. Matsumoto A. (2014 ). SPARC was overexpressed in human endometrial cancer stem-like cells and promoted migration activity. Gynecol. Oncol. 134 356–363.

    Not in our library10.1016/j.ygyno.2014.04.009

  155. 155.

    Zhang H. Lu H. Q. Xiang L. S. Bullen J. W. Zhang C. Z. Samanta D. (2015a ). HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc. Natl. Acad. Sci. U.S.A. 112 E6215–E6223.

    Not in our library10.1073/pnas.1520032112

  156. 156.

    Zhang H. Yang Y. A. Wang Y. F. Gao X. P. Wang W. M. Liu H. (2015b ). Relationship of tumor marker CA125 and ovarian tumor stem cells: preliminary identification. J. Ovarian Res. 8:19.

    Not in our library10.1186/s13048-015-0132-8

  157. 157.

    Zheng Y. H. Zou F. Y. Wang J. J. Yin G. F. Le V. Fei Z. W. (2015 ). Photodynamic therapy-mediated cancer vaccination enhances stem-like phenotype and immune escape. Which can be blocked by thrombospondin-1 signaling through CD47 receptor protein. J. Biol. Chem. 290 8975–8986.

    Not in our library10.1074/jbc.m114.624965

  158. 158.

    Zhou N. Wang R. Zhang Y. Z. Lei Z. Zhang X. H. Hu R. B. (2015 ). Staurosporine induced apoptosis may activate cancer stem-like cells (CD44(+)/CD24(-)) in MCF-7 by upregulating mucin1 and EpCAM. J. Cancer 6 1049–1057.

    Not in our library10.7150/jca.12501

  159. 159.

    Zhou W. C. Ke S. Q. Huang Z. Flavahan W. Fang X. G. Paul J. (2015 ). Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat. Cell Biol. 17 170–182.

    Not in our library10.1038/ncb3090

  160. 160.

    Zhou Y. Zhu Y. Fan X. Zhang C. Wang Y. Zhang L. (2017 ). NID1, a new regulator of EMT required for metastasis and chemoresistance of ovarian cancer cells. Oncotarget 8 33110–33121.

    Not in our library10.18632/oncotarget.16145

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