Vascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi's sarcoma cells

Recent evidence suggesting vascular endothelial growth factor-C (VEGF-C), w hich is a regulator of lymphatic and vascular endothelial development, rais ed the question whether this molecule could be involved in Kaposi's sarcoma (KS), a strongly angiogenic and inflammatory tumor often associated with i nfection by human immunodeficiency virus-1. This disease is characterized b y the presence of a core constituted of three main populations of "spindle" cells, having the features of lymphatic/vascular endothelial cells, macrop hagic/ dendritic cells, and of a mixed macrophage endothelial phenotype. In this study we evaluated the biological response of KS cells to VEGF-C, u sing an immortal cell line derived from a KS lesion (KS IMM), which retains most features of the parental tumor and can induce KS-like sarcomas when i njected subcutaneously in nude mice. We show that VEGFR-3, the specific rec eptor for VEGF-C, is expressed by KS IMM cells grown in vitro and in vivo. In vitro, VEGF-C induces the tyrosine phosphorylation of VEGFR-2, a recepto r also for VEGF-A, as well as that of VEGFR-3. The activation of these two receptors in KS IMM cells is followed by a dose-responsive mitogenic and mo togenic response. The stimulation of KS IMM cells with a mutant VEGF-C unab le to bind and activate VEFGR-2 resulted in no proliferative response and i n a weak motogenic stimulation, suggesting that VEGFR-2 is essential in tra nsducing a proliferative signal and cooperates with VEGFR-3 in inducing cel l migration. Our data add new insights on the pathogenesis of KS, suggesting that the in volvement of endothelial growth factors may not only determine KS-associate d angiogenesis, but also play a critical role in controlling KS cell growth and/or migration and invasion.