PLATELET-ACTIVATING-FACTOR PRODUCED IN-VITRO BY KAPOSIS-SARCOMA CELLSINDUCES AND SUSTAINS IN-VIVO ANGIOGENESIS

Imbalance in the network of soluble mediators may play a pivotal role in the pathogenesis of Kaposi's sarcoma (KS), fn this study, we demons trated that KS cells grown in vitro produced and in part released plat elet activating factor (PAF), a powerful Lipid mediator of inflammatio n and cell-to-cell communication, IL-1, TNF, and thrombin enhanced the synthesis of PAF. PAF receptor mRNA and specific, high affinity bindi ng site for PAF were present in KS cells. Nanomolar concentration of P AF stimulated the chemotaxis and chemokinesis of KS cells, endothelial cells, and vascular smooth muscle cells, The migration response to PA F was inhibited by WEB 2170, a hetrazepinoic PAF receptor antagonist, Because neoangiogenesis is essential for the growth and progression of KS and since PAF can activate vascular endothelial cells, we examined the potential role of PAF as an instrumental mediator of angiogenesis associated with KS, Conditioned medium (CM) from KS cells (KS-CM) or KS cells themselves induced angiogenesis and macrophage recruitment in a murine model in which Matrigel was injected subcutaneously, These e ffects were inhibited by treating mice with WEB 2170, Synthetic PAF or natural PAF extracted from plasma of patients with classical RS also induced angiogenesis, which in turn was inhibited by WEB 2170, The act ion of PAF was amplified by expression of other angiogenic factors and chemokines: these included basic and acidic fibroblast growth factor, placental growth factor, vascular endothelial growth factor and ifs s pecific receptor flk-1, hepatocyte growth factor, KC, and macrophage i nflammatory protein-2 Tre;atment with WEB 2170 abolished the expressio n of the transcripts of these molecules within Matrigel containing KS- CM. These results indicate that PAF may cooperate with other angiogeni c molecules and chemokines in inducing vascular development in KS.