Kaposi's sarcoma is a tumor in which the lesion predominantly consists of aberrant vascular proliferation. The tumor tissue, or KS-derived spindle cells, when placed subcutaneously in the nude mouse, induces a vascular lesion resembling Kaposi's sarcoma and is of mouse tissue origin. Further, the lesion demonstrates a delayed (12 hr) vascular hyperpermeability response. Thus, this tumor provides an excellent model system to not only understand more about the tumor itself, but also the signals involved in angiogenesis, and to study inhibitors that could later be used for therapy of a variety of diseases, including vascular diseases, malignancy and inflammatory disease. Primary mediators of angiogenesis include: (i) fibroblast growth factors, basic and acidic, both of which lack signal peptide and thus are not secreted, and (ii) vascular endothelial cell growth factor or vascular permeability factor (VDGF/VPF) which has signal peptide and is secreted. VEGF/VPF and FGFs are produced by Kaposi's sarcoma derived spindle cells. Secondary mediators of angiogenesis (such as TNF, TFG-alpha and beta, angiogenin etc) induce angiogenic lesions only in vivo. Thus, these factors must exert their response through the induction of primary mediators. KS derived spindle cells produces many of these cytokines (TGF-beta, IL-1 and IL-6). Further, steroid hormones regulate cytokine expression which in turn regulates angiogenic factors. Alternatively steroid hormones may directly regulate angiogenic factors. We have also shown that glucocorticoids pardoxically enhance IL-6 expression, which in turn upregulates VEGF/VPF. Based on the above, we propose to study the following using vascular endothelial cells and vascular smooth muscle cells as controls: (1) The expression of known primary mediators of angiogenesis in KS-derived spindle cells and their regulation by steroid hormones and cytokines; (ii) Define further the presence or absence of a novel angiogenic factor expressed by KS-derived spindle cells; (iii) Study the transduction pathway of IL-6 and VEGF/VPF; (iv) Define the mechanism of the paradoxical upregulation of IL-6 with glucocorticoids in KS derived spindle cells and compare to other cell types.
