Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth : an in vivo study on 29 tumors

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 1999-06, Vol.77 (6), p.505-510
• Main Authors: BRIEGER, J, WEIDT, E. J, SCHIRMACHER, P, STÖRKEL, S, HUBER, C, DECKER, H. J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological and medical sciences; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - genetics; Clear cells; Endothelial Growth Factors - genetics; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Kidney Neoplasms - blood supply; Kidney Neoplasms - genetics; Kidneys; Ligases; Lymphokines - genetics; Male; Medical sciences; Middle Aged; Neovascularization, Pathologic - genetics; Nephrology. Urinary tract diseases; Proteins - genetics; Tumor Suppressor Proteins; Tumors of the urinary system; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Von Hippel-Lindau Tumor Suppressor Protein
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s001099900022

Tumors associated with the VHL (von Hippel-Lindau) disease, such as hemangioblastomas and renal carcinomas and their sporadic counterparts, are cystic and well vascularized. Mutations of the VHL tumor-suppressor gene and elevated levels of vascular endothelial growth factor (VEGF) have been described in these tumors. The upregulation of VEGF has been shown in vitro as a consequence of alteration of the VHL gene. No comprehensive in vivo analysis has yet been carried out of the factors affecting tumor growth, vascularization, VEGF, and VHL expression. We performed immunohistochemistry and mRNA studies on primary sporadic renal carcinomas and matching normal renal tissue. We semiquantitatively analyzed 29 renal carcinomas (22 clear cell, 5 chromophilic, 2 chromophobic tumors) for VHL mRNA, and VEGF expression for morphology and tumor size. Immunohistochemistry was carried out for VEGF protein expression, vascularization, and macrophage infiltration. Vascularization of the chromophilic renal carcinomas was lower than that of the clear cell type of renal carcinoma. Low VEGF protein expression was seen in four of the five chromophilic renal carcinomas. We found two groups of clear cell renal cell carcinoma: one with reduced VHL mRNA and increased VEGF mRNA, and the other without significantly altered VHL or VEGF mRNAs. Tumor vascularization was correlated with VEGF protein and seemed to be independent of macrophage infiltration. Our in vivo findings support the inverse relationship between the regulation of VHL and that of VEGF. Our data also indicate that there may be an VHL-independent pathway for the induction of tumor vascularization.