Melanoma, which accounts for only 4% of all skin cancers, but 75% of skin cancer-related deaths, continues to rise at an alarming rate worldwide. When a melanoma is detected and resected at an early stage, the cure rate for patients is favorable. However, the response rate of patients with metastatic melanoma to chemotherapy is less than 15%, and biological therapies have limited efficacy. Therefore, identification of genes that can serve as therapeutic targets for advanced-stage melanoma is crucial. The cell adhesion molecules N-cadherin, MCAM, and Beta3 integrin have been postulated to represent melanoma progression markers; yet, little is known regarding whether they may constitute valuable therapeutic targets for the disease. Furthermore, no studies conducted to date have examined the expression and function of these three molecules in concert in melanoma. The results of our whole-genome and tissue microarray profiling illustrate N-cadherin, MCAM, and Beta3 integrin expression in the distinct stages of melanoma progression. We demonstrate that N-cadherin and Beta3 integrin are melanoma progression markers, but MCAM is not. Furthermore, greater than 95% of metastatic melanomas analyzed in our study express at least one of the three adhesion molecules, and 50% express all three.
Our next objective was to determine whether inhibition of N-cadherin, MCAM, or Beta3 integrin impairs melanoma cell proliferation, migration, and/or invasion. We hypothesized that due to redundancy in the functions of N-cadherin, MCAM, and Beta3 integrin, simultaneous inhibition of all three molecules may elicit the most effective therapeutic response. We demonstrate that inhibiting expression of N-cadherin, MCAM, or Beta3 integrin decreases melanoma cell proliferation. However, inhibiting their expression in parallel does not augment the anti-proliferative effect. In contrast, downregulation of N-cadherin, MCAM, and Beta3 integrin in parallel inhibits melanoma cell migration and invasion to a significantly greater extent than targeting each gene alone. Our results indicate that of the three adhesion molecules, MCAM and Beta3 integrin play the most pronounced role in migration and invasion, and therefore, in combination, may represent the most promising therapeutic targets. The data presented in this dissertation provide the foundation for future clinical studies that target adhesion molecules in advanced-stage melanoma patients.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-10242006-104213 |
| Date | 24 October 2006 |
| Creators | Hurst, Kelly Watson |
| Contributors | Cary Wu, Dorothea Becker, Marie C. Defrances, Alan Wells, Jennifer Grandis |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-10242006-104213/ |
| 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 University of Pittsburgh 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. |
Page generated in 0.0016 seconds