Vascular endothelial growth factor expression, angiogenesis, and necrosis in renal cell carcinomas

Rapidly growing tumors often develop necrosis. In the present study the exp ression of vascular endothelial growth factor (VEGF) was investigated and c ompared to microvessel density and necrosis of renal cell carcinomas. In th e tumor-host interface the microvessel density was significantly increased compared to central tumor areas. Tumor necrosis was associated with a decre ase of microvessel density and an increase of the VEGF protein expression w ithin the perinecrotic rim. VEGF protein was focally upregulated in vital t umor tissue. An increase of the apoptotic rate of endothelia and vital tumo r tissue in tumors with necrosis could not be detected. VEGF((121,165)) mRN A was decreased in proliferatively active carcinomas compared to less proli ferative tumors. Multicellular renal cell cancer spheroids as a model of ch ronic hypoxia developed central apoptosis but no necrosis. VEGF was upregul ated in the spheroid. Tumor microvessels expressed matrix metalloproteinase -2 and -9 and an incomplete pericyte covering in comparison to tumor-free tissue indicating immature active angiogenesis. We conclude that highly pro liferative renal cell carcinomas outgrow their vascular supply and develop chronic hypoxia inducing a decrease of proliferation and an increase of VEG F expression. However, chronic hypoxia does not cause significant necrosis or apoptosis. Tumor necrosis is more likely induced by acute hypoxia due to immature microvessels. Furthermore, VEGF expression associated with concom itant tumor necrosis may help identify renal cell carcinomas susceptible to antiangiogenic therapy.