Tumour suppressors and hypoxia pathways in cancer


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Peter Ratcliffe
University of Oxford, UK

Abstract

<p>Tumour hypoxia is associated with poor prognosis. However, hypoxia may occur in tumours as a consequence of rapid growth, so that cause and effect can be difficult to distinguish. New opportunities for analysing this question have arisen from molecular insights into the hypoxia signaling pathways, and the recognition that these pathways are perturbed by mutations associated with certain hereditary cancer syndromes.</p><p>Many transcriptional responses to hypoxia are mediated by hypoxia inducible factor (HIF) a transcription factor that is regulated by the post-translational hydroxylation of HIF-alpha subunits by a series of non-haem Fe(II) and 2-oxoglutarate (2-OG) dependent dioxygenases. In the presence of oxygen, prolyl hydroxylation at residues within a central degradation domain of HIF-alpha promotes binding to the von Hippel Lindau tumour suppressor (pVHL) E3 ubiquitin ligase and hence proteolytic inactivation. </p><p>Cancer-associated mutations have now been identified in several genes affecting the HIF hydroxylase-VHL pathway. Loss-of-function VHL mutations block proteolytic regulation of HIF-alpha and up-regulate the HIF pathway. Germline mutations in the genes encoding fumarate hydratase (FH) and succinate dehydrogenase (SDH) subunits b, c and d have been identified in hereditary leiomyomatosis and renal cell cancer and in hereditary paragangliomatosis respectively. Heterozygous somatic mutations in NADPH-linked isocitrate dehydrogenases (IDH 1 and 2) have been found at high frequency in certain types of glioblastoma. Whilst IDH mutations restrict availability of 2-OG, FH and SDH mutations cause accumulation of fumarate and succinate that compete with 2-OG; all reduce HIF hydroxylation and hence upregulate the HIF pathway.  </p><p>Thus, genetic dysregulation at several points in the HIF hydroxylase–VHL pathway has been implicated in tumour predisposition or progression. Nevertheless each of these events potentially affects other processes – the presentation will review current data on the oncogenic role or otherwise of these pathways. </p><br>