Best Practice & Research Clinical Endocrinology & Metabolism
4VHL Disease
Section snippets
Clinical subtypes of disease
Von Hippel Lindau (VHL) disease is a hereditary familial cancer with an incidence of 1 in 36,000 live births.1, 7 VHL disease predisposes an individual to the development of different types of benign and malignant tumours in bilateral and multicentric forms. It is characterised by central nervous system, especially cerebellum, and retinal haemangioblastomas, clear-cell renal cell carcinoma and phaeochromocytoma or paraganglioma. A variety of other lesions have been associated with VHL disease
Genetic and molecular functions of VHL protein
There has been enormous progress in the past few years on the physiological role of VHL. In this section, we present a summary of the multiple functions ascribed to the VHL protein, which are likely to contribute to its role as a tumour suppressor.
Future of research: therapeutic implications
VHL mutant tumours are highly angiogenic and produce high levels of VEGFA.89 These observations can now be understood in light of the role of VHL in regulating HIF and have naturally developed into targets for therapy in these tumours, especially renal cancers. The use of angiogenic inhibitors (sorafenib and sunitib) or VEGF antibodies are now part of the standard treatment course of these tumours with superior responses compared to conventional chemo- or immunotherapy used for these cancers.89
Conclusions
Accumulating evidence over the past years has established the role of HIFα, especially HIF2α, in VHL-mutant tumours such as haemangioblastomas and renal carcinomas. At the same time, a number of HIF-independent VHL functions are being uncovered. Both spontaneous human mutations and animal models have pointed to a relevant role of these other functions to the pathogenesis of VHL-related tumours, especially phaeochromocytomas/paragangliomas (Fig. 1). While it has been long known that tumoural
Acknowledgements
PLMD is a recipient of a Voelcker Foundation Young Investigator Award and is supported by the Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (NIH-P30 CA54174).
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