Tenascin-C Modulates Matrix Contraction via Focal Adhesion Kinase– and Rho-mediated Signaling Pathways

Midwood, Kim S.; Schwarzbauer, Jean E.

doi:10.1091/mbc.e02-05-0292

Cited by 130 publications

(136 citation statements)

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“…Statistical analysis showed that fTn-C expression is associated with liver metastases of pancreatic cancers. These findings are in accordance with the reports from Midwood and co-workers (16,17). Moreover, in these metastatic cancers, fTn-C formation was associated with MMP-2 activation, suggesting that MMP-2 may contribute to Tn-C organization.…”

Section: Discussionsupporting

confidence: 92%

Role of fibrillar Tenascin-C in metastatic pancreatic cancer

Li¹

2009

Int J Oncol

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Abstract.Interaction of cancer cells with stroma cells facilitates tumor progression by rebuilding the existing extracellular matrix (ECM) microenvironment. In the tumor, upregulation of Tenascin-C (Tn-C) expression potentially can alter tumor behavior. However, the molecular mechanisms by which tumor-stroma interactions affect the tumor microenvironment have not been well characterized. In this study, we analyzed the expression of fibrillar Tn-C (fTn-C) in human metastatic pancreatic cancers. After co-culturing two pancreatic cancer cell lines, highly metastatic BxPc3 cells and nonmetastatic PaCa2 cells, with stromal fibroblasts (SF), we evaluated the roles of matrix metalloproteinase 2 (MMP-2) activation and SF in promoting Tn-C organization. Next, we evaluated whether fibrillar Tn-C promotes pancreatic cancer cell movement using cell adhesion and migration assays. Finally, we observed the relationship between MMP-2 activation and fTn-C formation in vivo by injecting the BxPc3 and PaCa2 cells into nude mice. We found that fTn-C was increased in metastatic pancreatic cancer. The fTn-C expression correlated with MMP-2 activity. In the in vitro co-culture, fTn-C organization was found only in BxPc3/SF co-cultures, and required the participation of active MMP-2. The fTn-C reduced cell adhesion and promote pancreatic cancer cell migration by decreasing the adhesive interactions between integrin ·6ß1 and the ECM. The in vivo tumorigenesis analysis showed that the fTn-C formation and active MMP-2 were significantly increased in the BxPc3 tumors, compared to the PaCa2 tumors. These results demonstrate that Tn-C deposition into the ECM requires participation of active MMP-2 and SF. The deposited Tn-C could promote pancreatic cancer progression. IntroductionTenascin-C (Tn-C) and fibronectin (FN) are glycoproteins of the extracellular matrix (ECM) that interact with each other and with other matrix molecules including collagen and heparan sulfate proteoglycans. FN is processed into an insoluble fibrillar matrix to which Tn-C binds either directly or indirectly via proteoglycans that bridge the two proteins (1). Both proteins contain sites that are recognized by cell surface receptors whose occupation allows the ECM to regulate the adhesion, differentiation, growth, and migration of cells. Tn-C interferes with the cell adhesive function of FN either by binding to FN and restricting access to its integrin binding sites (2), or by binding to cell receptors and altering their responsiveness to FN (3,4). Tn-C is transiently expressed during fetal development, and is absent or greatly reduced in most adult tissues. It is increased in some pathological conditions, including inflammation, wound healing and cancer. Tn-C is highly expressed in the majority of malignant solid tumors, including those originating from the brain, breast, colon, prostate and pancreas. Tn-C is secreted by both cancer cells and stromal cells (5). The most prominent effects of Tn-C are anti-adhesion (6) and inhibition of cell attachment (7), both of which...

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Section: Discussionsupporting

confidence: 92%

Role of fibrillar Tenascin-C in metastatic pancreatic cancer

Li¹

2009

Int J Oncol

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“…Almost all known binding sites lie in the fibronectin type III repeats or the fibrinogen globe, but evidence has been reported suggesting that the EGF-like repeats act as low affinity ligands for EGF receptors (15). As a consequence, cell interactions with tenascin-C are quite complex, and several signaling mechanisms have been identified, including recent observations that tenascin-C blocks focal adhesion kinase-and Rho-mediated signaling pathways activated by fibronectin (2,16,17) as well as stimulating Wnt and other growth-promoting pathways (18). For a detailed discussion of these mechanisms, please refer to Gertrude Orend's recent review (4).…”

Section: About the Familymentioning

confidence: 99%

Meet the Tenascins: Multifunctional and Mysterious

Hsia

Schwarzbauer

2005

Journal of Biological Chemistry

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148

112

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“…Tenascin-C not only interacts with other ECM molecules, such as perlecan and fibronectin, but also cellsurface receptors including integrins a2b1, avb3 and a9b1, annexin II, and syndecan (40). It is proposed that the inhibition of syndecan-4, Rho, and FAK in cell spreading and the fibronectin matrix assembly by tenascin-C are major mechanisms for cell detachment operating in solid tumors (41,42). However, T lymphocytes express little syndecan-4 (43,44).…”

Section: Discussionmentioning

confidence: 99%