UP-REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR AND ITS RECEPTORSIN VON HIPPEL-LINDAU DISEASE-ASSOCIATED AND SPORADIC HEMANGIOBLASTOMAS

Capillary hemangioblastoma is the most frequent manifestation of the a utosomal dominantly inherited von Hippel-Lindau (VHL) disease but also presents as a nonfamilial, sporadic vascular tumor. Hemangioblastomas are characterized by a dense network of capillaries in association wi th cysts. To investigate the mechanisms underlying neovascularization and cyst formation, we analyzed eight VHL disease-associated and five sporadic hemangioblastomas. Histologically, both tumor types showed a similar phenotype. The capillaries expressed the endothelial cell mark ers von Willebrand factor and CD31 antigen. We investigated the expres sion of vascular endothelial growth factor (VEGF), an endothelial cell -specific mitogen which is also known to induce vascular permeability in vivo, and its high affinity tyrosine kinase receptors flt-1 and KDR . Northern blot and in situ hybridization analysis revealed significan t up-regulation of VEGF and VEGF receptor expression in VHL disease-as sociated and sporadic hemangioblastomas compared to normal brain and t umor stromal cells as sites of abundant VEGF transcription. Endothelia l cells did not express detectable amounts of VEGF mRNA but coexpresse d flt-1 and KDR. By immunohistochemistry, VEGF protein was detectable in the tumor interstitium and was found to be concentrated around capi llaries. Performing reverse transcription-PCR, we demonstrated that VE GF(121) and VEGF(165) were the splice variants predominantly expressed , whereas mRNA encoding VEGF(189) was present at smaller amounts. Our findings suggest that, in VHL disease-associated and sporadic hemangio blastomas, VEGF(121) and VEGF(165) are secreted by stromal cells and i nteract with the corresponding VEGF receptors expressed on tumor endot helial cells. This paracrine mechanism may mediate neovascularization and cyst formation in capillary hemangioblastomas.