Fig. 3.

Proposed HIF-dependent and HIF-independent functions of pVHL in VHL-associated tumorigenesis. A clinical hallmark of VHL disease is the development of CNS hemangioblastomas and clear cell carcinoma of the kidney (CC-RCC). Panel A: Pathogenesis of VHL-associated hemangiomas/hemangioblastomas. Mice with germ line mutations in pVHL (VHL+/−) are predisposed to the development of liver hemangiomas (photograph). Genetic studies in mice demonstrated exclusive HIF-2-dependence, which is in line with HIF expression studies in human hemangioblastomas. Panel B: Pathogenesis of VHL-associated renal cancer. The pathogenesis of CC-RCC is more complex and most likely involves both, HIF-dependent and HIF independent functions of pVHL, as well as other genetic events that lead to malignant transformation. Shown is the macroscopic (A) and microscopic (B) appearance of large cortical renal cysts in mouse kidneys with pVHL inactivation (arrows and stars). (B), magnification x100. (C) and (D), human CC-RCC; (C), gross photography; (D), clear cell histology (arrows), magnification x400. Images (C) and (D) were kindly provided by Dr. John Tomaszewski, Department of Pathology, University of Pennsylvania, Philadelphia, PA.