Title
VHL and HIF signalling in renal cell carcinogenesis
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Edinburgh ,
Subject
Human medicine
Source (journal)
The journal of pathology. - Edinburgh
Volume/pages
221(2010) :2 , p. 125-138
ISSN
0022-3417
ISI
000278209800002
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2 appears to be more oncogenic than HIF-1, in that HIF-2 activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1, more than HIF-2, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.
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