Clinical and experimental evidence imply that Kaposi's sarcoma (KS) is initially an angioproliferative hyperplasia that employs autocrine and paracrine growth loops to facilitate progression to a highly angiogenic sarcoma. Because KS cells both produce and respond to angiogenic factors, KS cells are both effectors and targets of angiogenic molecules. The KS milieu is characterized by elevated levels of proinflammatory cytokines and persistent inflammation, conditions which result in high production of reactive oxygen and nitrogen species. Recent studies from our laboratory have shown in situ evidence of ongoing oxidative stress within lesional cells of patients' KS biopsies. Other studies from our laboratory have shown that cultured KS strains obtained from these KS biopsies fail to upregulate cytoprotective enzymes and associated cofactors after oxidant challenge. These clinical findings and our experimental data indicate that KS arises due to a cellular inability to prevent the deleterious, tumorigenic consequences of oxidative stress. Oxidative stress promotes tumor formation by supporting cell proliferation, while it simultaneously inactivates key antioxidant and DNA repair enzymes, and induces a pro-angiogenic environment. Based on our results and reported clinical and experimental data, we have developed the following hypothesis: The angiogenic factors VEGF and bFGF in conjunction with oxidant stress facilitate the development and progression of Kaposi's sarcoma. Furthermore, agents that act as antioxidants or angiostatics will disrupt development of the KS tumorigenic phenotype. This hypothesis will be tested using both in vitro (cultured KS and human endothelial cells) and in vivo (KS cells transplanted in nude mice).
Aim 1 studies will characterize the role of oxidative stress in development and progression of the KS tumorigenic phenotype.
Aim 2 studies will investigate the ability of pharmacologic agents to suppress the KS tumorigenic phenotype in vitro.
Aim 3 studies will evaluate the ability of controlled-release pharmacologic agents to inhibit growth of KS tumors in vivo. The proposed studies use a molecular approach to identify mechanisms by which expression of the complete angiogenic cytokines VEGF and bFGF and reactive species converge to facilitate KS development and progression. Elucidation of these interactions will not only clarify KS pathogenic mechanisms, but will also identify sites for KS therapeutic intervention.
