The role of lipid second messengers in angiogenesis and the vascular endothelium response to radiation.

Abstract

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.