TY - JOUR
T1 - VHL and HIF signalling in renal cell carcinogenesis
AU - Baldewijns, Marcella M.
AU - van Vlodrop, Iris J. H.
AU - Vermeulen, Peter B.
AU - Soetekouw, Patricia M. M. B.
AU - van Engeland, Manon
AU - de Bruine, Adriaan P.
PY - 2010/6
Y1 - 2010/6
N2 - 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
AB - 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
KW - HIF
KW - VHL
KW - renal cell carcinoma
KW - targeted therapy
U2 - 10.1002/path.2689
DO - 10.1002/path.2689
M3 - Article
C2 - 20225241
SN - 0022-3417
VL - 221
SP - 125
EP - 138
JO - Journal of Pathology
JF - Journal of Pathology
IS - 2
ER -