Transforming growth factor beta 1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in patients wi th VHL disease and in the majority of patients with sporadic clear cell ren al carcinoma (RCC), Overexpression of transforming growth factor (TGF) beta 1 has been observed in patients with several cancers, including RCCs, with serum and urine levels correlating inversely with prognosis. We have demon strated that the VHL tumor suppressor gene product represses TGF-beta 1 mRN A and protein levels ( approximate to 3-4-fold) in 786-O RCC cells by decre asing the TGF-beta 1 mRNA half-life. Exogenously added TGF-beta 1 did not s uppress the growth of 786-O cells in vitro, nor did the addition of neutral izing antibody (Ab) against TGF-beta have any effect, Indeed, 786-O cells w ere found to express no TGF-beta type II receptor protein, thus allowing th em to escape from the negative growth control of TGF-beta 1, In contrast to the ill vitro data, neutralizing Ab to TGF-beta inhibited tumorigenesis an d, in some cases, regressed established 786-O tumors in athymic mice. Immun ohistochemistry for von Willebrand's factor revealed a 3-4-fold lower tumor microvessel count in the mice treated with TGF-beta Ab compared to control s, suggesting that the Ab was inhibiting angiogenesis, Our findings indicat e that TGF-beta 1 is a novel target for the VHL tumor suppressor and that a ntagonizing its paracrine action may provide novel avenues for treatment of RCCs as well as other tumors that secrete TGF-beta 1.