VASCULAR ENDOTHELIAL GROWTH-FACTOR UP-REGULATES ITS RECEPTOR FMS-LIKE-TYROSINE-KINASE-1 (FLT-1) AND A SOLUBLE VARIANT OF FLT-1 IN HUMAN VASCULAR ENDOTHELIAL-CELLS

The growth of solid tumors and the formation of metastases are depende nt on neoangiogenesis, One of the most important factors in inducing t he formation of new blood vessels is the vascular endothelial growth f actor (VEGF), which acts specifically on endothelial cells, VEGF is ex pressed and secreted by almost all solid tumors, The molecular mechani sms leading to enhanced production of this angiogenic mitogen are many fold and have been elucidated to some degree, Two VEGF receptors, fats -like tyrosine kinase 1 (FLT-I) and KDR, have been identified almost s pecifically on human endothelial cells, They are expressed preferentia lly in the proliferating endothelium of vessels lining and/or penetrat ing solid tumors, whereas they are almost undetectable by convenient m ethods in vessels of healthy tissue, However, the underlying mechanism s are not understood, We could show that media conditioned by various cancer cell lines grown under hypoxic conditions mere able to up-regul ate expression of FLT-1 mRNA and protein but not of KDR mRNA, Furtherm ore, up-regulation of a shorter mRNA species was observed that most pr obably codes for the soluble variant of FLT-1. These effects were comp letely inhibited by VEGF-neutralizing extracellular VEGF receptor doma ins, The effect could be mimicked by adding recombinant VEGF instead o f conditioned cancer cell medium to the endothelial cell cultures. Bot h mutant VEGF, which activates only KDR, and placenta growth factor, w hich activates only FLT-1, were able to enhance FLT-1 expression, VEGF -stimulated FLT-1 mRNA expression was inhibited by actinomycin D. Thes e data suggest that VEGF itself is the main factor secreted by tumor c ells that is able to enhance the expression of its receptor FLT-1 and of a soluble variant of FLT-1 in endothelial cells.