Studies demonstrating the structural and functional specificities of various cell-ECM attachment sites will be continued, with particular emphasis on altered molecular mechanisms of cell adhesion, cell de-adhesion, and invasion in transformed cells. Our working hypotheses are: 1) distinct, specific cell surface receptors are involved in organizing cell attachments to fibronectin and collagen during dynamic processes of cell adhesion and invasion, 2) ligands such as fibronectin can help to regulate the distribution of their receptors and the cytoskeleton, and 3) localized cell surface proteases are responsible for cell contact-related dissolution of the ECM, which permits invasion. Recent studies have demonstrated the existence of transformation-induced cell surface proteases that degrade fibronectin and collagen at cell contact sites. Thus, the immediate goals of the present proposal are to use monoclonal antibody probes to localize these transformation-sensitive, invasion-associated proteases, to identify protease structural domains, and to perturb molecular interactions involving proteases. By this we plan to determine the possible role of these proteases in transformed cell invasion or as indicators of the metastatic potential of tumor cells. The proposed studies will also define possible collagen attachment sites at the electron microscopic level, and determine whether such attachments function via collagen receptors. To do this, we will use in situ localization and antibody inhibition approaches similar to those used for the characterization of the fibronectin-receptor association. Possible regulatory roles of fibronectin and collagen in the organization of attachment sites and in the invasion of the tumor cells will then be studied by allowing these molecules to bind to the cell surface and inhibiting their binding using specific monoclonal antibody probes and synthetic peptides. More specifically, we will seek to determine: 1) the molecular structure and biochemical properties of cell surface proteases by the use of hybridoma technology, 2) the roles of cell surface proteases in transformation and invasion into fibronectin and collagen substrata, 3) the expression and localization of cell surface receptors for collagen and fibronectin at distinct attachment sites, 4) the regulatory roles of fibronectin and collagen in the organization of adhesion sites in transformed cells, and 5) the in vivo biological significance of cell surface proteases or receptors in migration and invasion of tumor cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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Georgetown University
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Tulley, Shaun; Chen, Wen-Tien (2014) Transcriptional regulation of seprase in invasive melanoma cells by transforming growth factor-? signaling. J Biol Chem 289:15280-96
Javidroozi, Mazyar; Zucker, Stanley; Chen, Wen-Tien (2012) Plasma seprase and DPP4 levels as markers of disease and prognosis in cancer. Dis Markers 32:309-20
Lu, Janice; Fan, Tina; Zhao, Qiang et al. (2010) Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer 126:669-83
Fan, Tina; Zhao, Qiang; Chen, John J et al. (2009) Clinical significance of circulating tumor cells detected by an invasion assay in peripheral blood of patients with ovarian cancer. Gynecol Oncol 112:185-91
Kennedy, Alanna; Dong, Huan; Chen, Donghai et al. (2009) Elevation of seprase expression and promotion of an invasive phenotype by collagenous matrices in ovarian tumor cells. Int J Cancer 124:27-35
Freudenberg, Jaclyn A; Chen, Wen-Tien (2007) Induction of Smad1 by MT1-MMP contributes to tumor growth. Int J Cancer 121:966-77
Ghersi, Giulio; Zhao, Qiang; Salamone, Monica et al. (2006) The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res 66:4652-61
Chen, Donghai; Kennedy, Alanna; Wang, Jaw-Yuan et al. (2006) Activation of EDTA-resistant gelatinases in malignant human tumors. Cancer Res 66:9977-85
Chen, Wen-Tien; Kelly, Thomas (2003) Seprase complexes in cellular invasiveness. Cancer Metastasis Rev 22:259-69
Chen, Wen-Tien; Kelly, Thomas; Ghersi, Giulio (2003) DPPIV, seprase, and related serine peptidases in multiple cellular functions. Curr Top Dev Biol 54:207-32

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