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

Abstract

Rapidly growing tumors often develop necrosis. In the present study the expression of vascular endothelial growth factor (VEGF) was investigated and compared to microvessel density and necrosis of renal cell carcinomas. In the tumor-host interface the microvessel density was significantly increased compared to central tumor areas. Tumor necrosis was associated with a decrease of microvessel density and an increase of the VEGF protein expression within the perinecrotic rim. VEGF protein was focally upregulated in vital tumor tissue. An increase of the apoptotic rate of endothelia and vital tumor tissue in tumors with necrosis could not be detected. VEGF(121,165) mRNA was decreased in proliferatively active carcinomas compared to less proliferative tumors. Multicellular renal cell cancer spheroids as a model of chronic hypoxia developed central apoptosis but no necrosis. VEGF was upregulated 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 proliferative renal cell carcinomas outgrow their vascular supply and develop chronic hypoxia inducing a decrease of proliferation and an increase of VEGF 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 concomitant tumor necrosis may help identify renal cell carcinomas susceptible to antiangiogenic therapy.

Understanding the Importance of Smart Drugs in Renal Cell Carcinoma

“…In addition, VEGF 121 mRNA levels were decreased in locally advanced tumors, compared with metastatic or small localised tumors [64,65]. Such a decrease in transcript levels had been noted previously in highly proliferative RCCs [66]. This finding could be due to an activation of 121 and 165 VEGF forms translation, leading to a reduced mRNA half-life.…”

Renal artery changes in patients with primary renal cell carcinoma

“…Such changes are usually attributed to some abnormalities in tumor vascularization. The data in the literature pointed out to the relationship between the presence and extent of tumor necrosis in RCC and different features including tumor size, cell type, nuclear grade as well as microvessel density and the expression of different markers [6]. However, there are no data about the relationship between fibromuscular dysplasia like changes and renal cell carcinoma.…”

Morphometric analysis of renal arteries in patients with renal cell carcinoma,

“…According to some authors, necrosis in RCC is attributed to a decrease in microvessel density and immaturity of microvessels with the possibility that tumor necrosis is a consequence of acute hypoxia [10,17]. However, the exact pathogenesis of tumor necrosis as well as the cause and nature of renal artery changes and the possible impact Tomic et al 10 on tumor necrosis have not yet been fully clarified [11,17].…”

“…Recently, the presence and extent of tumor necrosis are also considered as a predictor of more aggressive tumor behavior and poorer prognosis [6,17]. The majority of authors suggest that decreased tumor microvessel density leads to chronic hypoxia of the tumor tissue, which then causes coagulative necrosis [10,17]. However, some authors suggest that pathologic changes in renal arteries could also be responsible for tumor necrosis in RCC [11,20].…”