HOST MICROVASCULATURE INFLUENCE ON TUMOR VASCULAR MORPHOLOGY AND ENDOTHELIAL GENE-EXPRESSION

We have previously demonstrated that vascular endothelial growth facto r-165 (VEGF), a tumor-secreted angiogenic factor, can acutely and chro nically induce fenestrations in microvascular endothelium (Cancer Res 1997, 57:765-772), Because the morphology and function of microvascula r endothelium differs from tissue to tissue, we undertook studies to e xamine whether the neovasculature in tumors also differed depending up on tumor location. Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and tno human glioblastomas (U87 and U251), I n addition,we studied Chinese hamster ovary cells stably transfected w ith human VEGF(165). As previously reported, tumors grown in the subcu taneous space had a microvasculature that was fenestrated and had open endothelial gaps, The identical tumors when grown in the brain also h ad fenestrated endothelium and vessels with open endothelial gaps, but they were drastically reduced in occurrence. Open endothelial gaps we re not seen in all tumors implanted in the brain (EMT and M1S), althou gh fenestrated endothelium was always seen, VEGF and VEGF receptors we re measured in tumors from both locations by immunoblotting and compet itive polymerase chain reaction, respectively. VEGF amount was not sig nificantly different between the tumor locations. Interestingly, total tumor vascular mRNA expression of both Flk-1 and Flt-1 was greater in tumor vessels derived from the brain compared with tumor vessels deri ved from subcutaneous tissues. These results demonstrate that the host microvascular environment determines the morphology and function of t he tumor vasculature and that endothelia from different tissues vary i n their ability to express the VEGF receptors given identical stimuli.