Transforming growth factor beta1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma

Abstract

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients with VHL disease and in the majority of patients with sporadic clear cell renal carcinoma (RCC). Overexpression of transforming growth factor (TGF) beta1 has been observed in patients with several cancers, including RCCs, with serum and urine levels correlating inversely with prognosis. We have demonstrated that the VHL tumor suppressor gene product represses TGF-beta1 mRNA and protein levels (approximately 3-4-fold) in 786-O RCC cells by decreasing the TGF-beta1 mRNA half-life. Exogenously added TGF-beta1 did not suppress the growth of 786-O cells in vitro, nor did the addition of neutralizing antibody (Ab) against TGF-beta have any effect. Indeed, 786-O cells were found to express no TGF-beta type II receptor protein, thus allowing them to escape from the negative growth control of TGF-beta1. In contrast to the in vitro data, neutralizing Ab to TGF-beta inhibited tumorigenesis and, in some cases, regressed established 786-O tumors in athymic mice. Immunohistochemistry for von Willebrand's factor revealed a 3-4-fold lower tumor microvessel count in the mice treated with TGF-beta Ab compared to controls, suggesting that the Ab was inhibiting angiogenesis. Our findings indicate that TGF-beta1 is a novel target for the VHL tumor suppressor and that antagonizing its paracrine action may provide novel avenues for treatment of RCCs as well as other tumors that secrete TGF-beta1.