Models of Von Hippel-Lindau tumor suppressor disease specific activity.

9553 Background: The Von Hippel-Lindau (VHL) syndrome is an autosomal dominant disorder characterized by mutations in a classical tumor suppressor gene (VHL). Clear cell renal cell carcinoma and hemangioblastoma without pheochromocytoma characterize VHL type 1 disease. VHL type 2 disease is characterized by the presence of pheochromocytoma and is further subdivided into type 2A (pheochromocytoma and hemangioblastoma), 2B (pheochromocytoma, renal cell carcinoma, and hemangioblastoma), and 2C (pheochromocytoma only). VHL has been implicated in cellular processes important for tumorigenesis, including cell cycle control, extra-cellular matrix remodeling, response to oxygen deprivation, and angiogenesis. The importance of VHL in each of these processes as they pertain to tumorigenesis is unknown. METHODS To address the hypothesis that pVHL performs multiple functions within the cell, and perturbation of individual functions via missense mutations contributes to the tissue specificity of the VHL syndrome tumors, we have generated a panel of VHL mutations representative of the VHL disease subtypes in both tissue culture and transgenic animal model systems by both transgenic and gene targeting approaches. RESULTS Embryonic stem cells which express only mutant forms of the VHL protein were examined in vitro for activation of the hypoxic response pathway, and demonstrate a restricted pattern of HIF1a and HIF2a activation, which correlates with predisposition to clear cell renal cell carcinoma. Furthermore, in teratomas derived from these ES cells on nude mice, we observed defects of tumor development, angiogenesis, as well as fibronectin deposition, which also correlate to the mutation of VHL expressed. CONCLUSIONS This strategy utilizes three models systems: tissue culture, xenograft, and in vivo animal models to create distinctions between uniquely tissue specific types of tumorigenesis. Our findings of regulated HIF expression and HIF target gene expression as well as effects on vasculogenesis mimic those observed in human disease and provides a molecular mechanism to account for the highly vascular phenotype of VHL associated tumors. No significant financial relationships to disclose.