KAPOSI SARCOMA-ANGIOMA CELL CYCLE--EVENTS &CONTROLS

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.