Hurst, Kelly Watson
(2006)
The Role of the Cell Adhesion Molecules N-cadherin, MCAM, and Beta 3 Integrin in Human Melanoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
24 October 2006 |
| Date Type: |
Completion |
| Defense Date: |
10 October 2006 |
| Approval Date: |
24 October 2006 |
| Submission Date: |
24 October 2006 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Adhesion Molecules; Melanoma; Therapeutic Targets |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-10242006-104213/, etd-10242006-104213 |
| Date Deposited: |
10 Nov 2011 20:03 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9508 |
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