Clear cell renal cell carcinoma (ccRCC) is by far the most common type of kidney cancer and is characterized by loss of the tumor suppressor gene von Hippel-Lindau (VHL). ccRCC patients with metastatic disease has poor prognosis and today's therapy is insufficient. The cytokine Transforming Growth Factor-beta (TGF-beta) has been extensively studied in tumor biology and is believed to serve a variety of functions in tumor progression. We have previously shown that inhibition of NOTCH signaling causes a reduced migratory and invasive capacity of ccRCC cells, at least partly by a cross-talk with the TGF-beta pathway. In the present study we aimed to further clarify the role of TGF-beta signaling in ccRCC. We investigated the effects of TGF-beta pathway modulation and showed that TGF-beta inhibition attenuates the invasive capacity of ccRCC cells. By performing expression profiling we obtained a gene signature of the TGF-beta induced response in ccRCC cells. The expression analyses revealed an extensive overlap between the TGF-beta response and genes regulated by the hypoxia inducible factor (HIF). The link between the hypoxic and the TGF-beta pathways was further corroborated by functional experiments, which demonstrated that TGF-beta pathway activity was attenuated upon reintroduction of functional VHL in ccRCC. (C) 2013 Elsevier Inc. All rights reserved,