The cell of origin and the nature of Kaposi sarcoma (KS) remain matters of controversy. A strong line of evidence supports an endothelial origin and the vasoproliferative dysmorphogenic rather than neoplastic character of this lesion. According to this concept, KS begins as lymphatic and blood vascular endothelial cells migrate through abnormally permeable vessel walls into a dissolving extracellular matrix. Radial lymphatic-venous communications are formed, subsequently lose their vascular definition, and along with spindle cell endothelial variants become enveloped in a hyperplastic sclerotic process which progresses up the vascular tree. This study using our human KS, angioma, and control endothelial cell lines, will examine the signals that make normally quiescent endothelial cells become migratory, proliferative, and vasodysformative, how these signals are transduced into cell cycle changes, and whether the pathologic process can be reversed. We will first determine whether KS cells differ from control endothelium in regard to the sequence of cell cycle events, nuclear activation products, and proliferative signal transduction through endocytic and exocytic pathways using multiparameter FACS (total DNA, BrdUrd incorporation, nuclear and cytoplasmic cycle-related proteins), competitive PCR (mRNA), and fluorometry (intracellular pH and Ca2+). We will next examine whether abnormal proliferative signals arise outside the KS cell during cell migration and specifically, whether enhanced proteolytic activity (or reduced protease inhibitor activity), in the extracellular matrix, as suggested in the development of angiomas, stimulates cell cycling and if so, how signal transduction proceeds and whether modulation of protease-inhibitor balance reverses the proliferative signal. Thus, these studies will determine whether KS cells have transformed or dedifferentiated to produce their own growth-migration signals, or whether they are responding to autocrine or paracrine growth- migration signals in an abnormal extracellular environment. At the same time, the events and control mechanisms in normal endothelial and angioma cells and their interaction with extracellular matrix dissolution- deposition imbalance will be elucidated and test systems and therapeutic approaches define for other vasoproliferative-dysmorphogenic processes, such as vascular malformations, angiopathies, atherosclerosis, and wound healing.
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