Renal cell carcinoma pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
Pathophysiology
Sporadic Clear Cell Renal Carcinoma
Although Von Hippel-Lindau (VHL), an autosomal dominant disorder, is characterized by the mutation of the VHL gene - a tumor suppressor gene - and the consequential development of renal clear cell carcinomas following the silencing of the remaining normal VHL gene, the gene itself has been identified to be similarly responsible of the development of sporadic forms of renal clear cell carcinomas.
VHL protein is an oxygen sensing regulator of hypoxic responses. It has a major role in binding and inhibiting transciptional activators hypoxia-induced factor (HIF) 1-alpha and 2-alpha via ubiquination and destruction using elongin proteins C and B that bind to cul2 protein of the ubiquitin ligase protein (cullin) family.(12,13,11,9,10,15,16,17,14) Normally, inhibition of HIF by VHL prevents the encoding of proteins that promote angiogenesis, such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-alpha), glucose receptors such as GLUT-1 glucose transporter, and carbonic anhydrase IX (CA9) which ensures acid-base balance.(9,10,0) Inhibition of VHL induces the overexpression of these proteins, mimicking hypoxemia, and facilitates the development of clear cell carcinoma.(0) The disease process is not believed to be due to the simple interaction between VHL protein and HIF. Other proteins are also thought to be involved in the process, including fibronectin(27), chaperonin TRiC/CCT(28), microtubules(29), and transcription factor Jade-1(30-32).
Familial Forms of Clear Cell Renal Carcinoma
The translocation and loss of chromosome 3p at the site 3p14 is hypothesized to be responsible for the development of renal clear cell carcinomas in other familial forms not related to VHL disease.(33)