This project aims to better understand the role of Src kinase on the development of colon cancer. Enhanced Src expression and activity are commonly elevated in colon cancer, with progressively higher activity observed as tumors progress and metastasize, however, the specific mechanism by which Src promotes cancer progression are still under investigation. First, we examined the potential for biological cooperativity between APC (adenomatous polyposis coli), a tumor suppressor often mutated in early stages of colon cancer, and elevated Src activity, using conditionally immortalized mouse colon epithelial cell lines, IMCE (APC +/min) and YAMC (APC +/+) as a model. The APC genotype did not affect the ability of Src to disrupt cell-cell junctions and promote cell invasiveness. However, IMCE cells exhibited increased capacity for oncogenic Src-mediated anchorage-independent proliferation as compared to YAMC cells. This property was correlated with enhanced รข-catenin expression and activity, but not with enhanced ERK phosphorylation. The selective Src inhibitor, AZD0530, was found to be effective in blocking both cell invasion and proliferation. Second, we investigated the possible role for one of the major Src substrates, CAS (Crk associated substrate) in epithelial cell polarization. Stable depletion of CAS did not affect proliferation on the colon epithelial cell lines Caco2 and HCA7, however it increased thee transepithelial cell resistance of Caco2 cells compared to control cells. Furthermore, fluorescently tagged CAS was shown to localize to cell-cell adhesions in polarized Caco2 cells.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-06232008-105114 |
| Date | 27 June 2008 |
| Creators | Lund, Sabata Silva Constancio |
| Contributors | Robert J. Coffey, M.D., Stephen R. Hann, Ph.D., Matthew J. Tyska, Ph.D., Ambra Pozzi, Ph.D., Steven K. Hanks, Ph.D. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-06232008-105114/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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