Adhesion molecules and cell surface proteases are integrally involved in cell migration and matrix invasion that occurs in the early phase of wound healing and all stages of tumor progression and metastasis. Among these transmembrane glycoproteins, type II transmembrane serine proteases (TTSPs) [seprase and dipeptidyl peptidase IV (DPP4)], type I transmembrane matrix metalloproteinase (MT1-MMP) and integrins are likely down-regulated in late phases of wound closure but such regulation is lost in tumors. To advance knowledge of the role of integrins and transmembrane proteases in tumor progression and metastasis, three specific aims are sought: (i) to define the integrin function in tumor growth and survival, (ii) to provide evidence for the catalytic activation of seprase and its novel truncated forms and to demonstrate their roles in malignant progression, and (iii) to examine the possibility that increased expression of cell surface proteases is required for successful metastatic colonization. Both spontaneous and experimental metastasis models will be used, that is, immuno-deficient mice will be inoculated with stable cell lines either supporting or suppressing [using RNA interference (RNAi) knockdown] the expression of specific genes. Gene expression profiling and proteomic analysis of membrane proteins of FACS-sorted tumor and host stromal cells in primary tumors and metastases generated from the two models will reveal a set of molecules that are crucial for pathways of cell growth, survival and organ-specific seeding, as well as proteolytic enzyme-dependent tumor growth, invasion and metastatic colonization. Engineered protein expression, RNAi knockdown, and peptide / antibody inhibitors will be used to assess the molecular requirements for pathways related with the metastatic process. Peptide inhibitors and single chain fragment variable (scFv) antibody phage-display libraries derived from cancer patients will be used to identify blockers for tumor progression and metastasis. The long-term goal of this project is to determine the molecular mechanisms underlying extracellular matrix degradation and cell adhesion of both tumor and stromal cells in major steps of the metastatic process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB002065-20
Application #
7146701
Study Section
Special Emphasis Panel (ZRG1-ONC-D (03))
Program Officer
Hunziker, Rosemarie
Project Start
1983-09-30
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
20
Fiscal Year
2007
Total Cost
$330,679
Indirect Cost
Name
State University New York Stony Brook
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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