Dr. Kaposi's sarcoma (KS) is recognized as the most common tumor in AIDS patients. As AIDS patients are living longer due to better treatment and reduction of their HIV-1 viral load and opportunistic infections, KS is becoming more common and problematic for physicians. The pathogenesis of KS is complex and unclear. Cytokine production, immunosuppression and HIV-related proteins have all been proposed as important in KS; however, none of these factors alone has been able to explain the pathogenesis of this disease. In this proposal, we combine these advances with our observation that KS tumor cells in vitro and in vivo overexpress the anti-apoptotic protein, Bcl-x. It is currently unknown if apoptosis-related proteins are involved in the pathogenesis of KS, and we hypothesize that overexpression of cell survival proteins contributes to the emergence of, or survival advantage and immunologic escape of, KS tumor cells thereby functioning in a critically important role in the pathogenesis of KS. We will first define the apoptosis-related proteins expressed in KS tumor cells both in vitro and in vivo and expand the studies to include endothelial cells (ECs, the likely progenitor cell in KS) and transformed ECs (T-ECs) to create a comprehensive picture of apoptosis proteins expressed in a series of cells that likely represent the progression to KS (ECs - T-EC - KS tumor cells). Once we have a coherent picture of which proteins are expressed, we will focus on determining how specific cell survival gene products are modulated and their functional significance KS tumor cells in vitro and determine if this increase contributes to their longevity and evasion of immunosurveillance. We will then extend this in vitro data and examine the veracity of the functional results using an in vivo model of KS with entirely human constituents for tumorigenicity assays. By completing these 3 aims over the next 5 years, we will make significant advancements in understanding neoplastic processes involved in the pathogenesis of KS, and gain new molecular insight to aid in the development of novel therapies targeting apoptosis-related proteins in KS tumor cells. Such new treatment options are important for AIDS patients who frequently develop this deadly neoplasm.
