The findings presented in this dissertation identify cytosolic phospholipase A2 (cPLA2) as a key component in tumor angiogenesis and the response of vascular endothelial cells to therapeutic doses of ionizing radiation (2-5 Gy). Through extensive experimental analysis, the described results demonstrate that cPLA2 activation leads to increased production of the lipid second messenger, lysophosphatidylcholine (LPC), and the subsequent downstream phosphorylation of the pro-survival kinases Akt and ERK1/2. Furthermore, LPC is frequently converted to lysophosphatidic acid (LPA) by an enzyme known as autotaxin. Once generated, LPA can then initiate its own pro-survival signaling cascades through various G protein-coupled receptors. The result of these collective events is increased tumor vascularization and radioresistance of tumor blood vessels which can significantly enhance tumor progression. In summary, this dissertation project implicates key regulatory roles for cPLA2 and lipid second messengers in 1) the vascular endothelium response to ionizing radiation and 2) tumor blood vessel formation. These data suggest that the inhibition of cPLA2, LPC, and LPA may significantly improve the treatment response of previously resistant tumors including lung cancer and glioblastoma.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11232009-154909 |
| Date | 24 November 2009 |
| Creators | Linkous, Amanda Gwynn |
| Contributors | Dennis Hallahan, M.D., Jin Chen, M.D., Ph.D., Michael Freeman, Ph.D, P. Charles Lin, Ph.D, John Oates, M.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-11232009-154909/ |
| 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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