The etiology, histogenesis and neoplastic nature of Kaposi's sarcoma have been controversial, but it is considered to be a multi-focal hemorrhagic spindle-cell neoplasm of multicentric origin. Suggested progenitor cells include smooth muscle and endothelial cells. The mechanism of cell transformation is unknown, but may be caused by paracrine cytokines which induce cell proliferation and dedifferentiation resulting in autocrine regulation of cytokines. Attempts to implicate known viruses as a direct cause of KS have been unsuccessful; however, viruses may act indirectly by inducing cytokine production which acts in a paracrine manner on progenitor cells. Supporting this hypothesis is the observation that supernatants from HCMV infected cells contain elevated levels of IL-6 and induce DNA replication in resting fibroblasts. Supernatants from HIV infected cells support endothelial cell proliferation possibly by expression of the TAT gene product. Our hypothesis is that HCMV and HIV act as cofactors in the development of KS. Infected monocytes and or macrophages (Mphi) produce cytokines which in turn induce proliferation in normal endothelium and smooth muscle cells. This hypothesis will be pursued by four specific aims: 1) identification of cytokines (growth factors) present in supernatants of HCMV and/or HIV infected monocytes and/or Mphi; and determination of their effect on the replication and phenotype of endothelial, smooth muscle and KS cells; 2) investigation of the mechanism by which HCMV and/or HIV induces the synthesis of cytokines and/or growth factors; 3) determination of the role of smooth cells in the muscle cells in the derivation of KS tumor cells and analysis of the effect of virus supernatants and specific cytokines on expression of contractile and cytoskeletal proteins; and 4) determination of the involvement in cell proliferation of the p34cdc2 protein kinase in normal smooth muscle and endothelial cells after stimulation with media from virus infected cells and specific cytokines such as IL-6. The effect of modulating cdc2 expression in endothelial, smooth muscle, and spindle cells on DNA synthesis and cell proliferation will be determined. These investigations will yield important information at the molecular level concerning the role of viruses and cytokines in modulating the cell cycle of smooth muscle and KS cells. Information at this level is essential for the ultimate control of cancer and cardiovascular disease.
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