VHL and HIF signalling in renal cell carcinogenesis

Marcella M. Baldewijns*, Iris J. H. van Vlodrop, Peter B. Vermeulen, Patricia M. M. B. Soetekouw, Manon van Engeland, Adriaan P. de Bruine

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

205 Citations (Web of Science)

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 alpha appears to be more oncogenic than HIF-1 alpha, in that HIF2 alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1 alpha, more than HIF-2 alpha, 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. Pathological Society of Great Britain and Ireland. Published by
Original languageEnglish
Pages (from-to)125-138
JournalJournal of Pathology
Volume221
Issue number2
DOIs
Publication statusPublished - Jun 2010

Keywords

  • HIF
  • VHL
  • renal cell carcinoma
  • targeted therapy

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