Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are expressed in AIDS-associated Kaposi's sarcoma

Kaposi's sarcoma is characterized by clusters of spindle-shaped cells that are considered to be tumor cells and by prominent vasculature. Whereas spin dle cells are most likely endothelial in origin, it remains controversial w hether they are of lymphatic or blood vascular derivation. To test the hypo thesis that the lymphangiogenesis factor vascular endothelial growth factor -C and its receptors, KDR and flt-4, are involved in the pathogenesis of Ka posi's sarcoma, we performed in situ hybridizations and immunofluorescent s tainings on human immunodeficiency virus-associated Kaposi's sarcoma, Spind le-shaped tumor cells strongly expressed KDR and flt-4 mRNA, Immunofluoresc ent staining confirmed expression of the flt-4 receptor in Kaposi's sarcoma cells, and double labeling revealed its colocalization with the endothelia l cell marker CD31. Vascular endothelial growth factor-C was strongly expre ssed in blood vessels associated with Kaposi's sarcoma. In vitro, human der mal microvascular endothelial cells also expressed vascular endothelial gro wth factor-C mRNA that was further upregulated by vascular permeability fac tor/vascular endothelial growth factor. Vascular endothelial growth factor- C potently stimulated the proliferation of Kaposi's sarcoma tumor cells in vitro. These results demonstrate important paracrine functions of vascular endothelial growth factor-C, produced by blood vessels, in the pathogenesis of cutaneous Kaposi's sarcoma, and suggest a lymphatic origin and/or diffe rentiation of Kaposi's sarcoma tumor cells.