ReviewActivation of the HIF pathway in cancer
Introduction
Maintaining oxygen homeostasis is a primary requirement constraining the development, growth and internal organisation of all large animals. The transcriptional complex hypoxia inducible factor (HIF) has emerged recently as a key regulator of these processes, mediating a wide range of cellular and physiological responses necessary to adapt to changes in oxygen tension.
This central physiological challenge of achieving a balance between oxygen supply and demand is recapitulated during the development of cancer, and several lines of evidence now demonstrate involvement of the HIF system in important aspects of tumour behaviour. First, HIF activation is very commonly observed within regions of solid tumours. Second, the range of genes that are known to be induced by HIF activation in cultured cells demonstrates a striking concordance with patterns of gene expression that have classically been associated with cancer. Third, HIF inactivation has been demonstrated to have important effects on the behaviour of model tumours.
In this review, we discuss recent work on the role of the HIF system in cancer and highlight issues raised by the activation of a major physiological pathway by genetic mechanisms that promote tumour development.
Section snippets
The HIF system
The HIF DNA binding complex is a heterodimer of alpha and beta subunits, both of which are basic helix-loop-helix transcription factors [1]. The β-subunit of HIF is a constitutive nuclear protein, which is critically involved in a range of transcriptional systems, and was first identified in the context of the xenobiotic response. HIF-1α and HIF-2α, in contrast, are regulatory subunits and are specific to the oxygen response pathway. In cells replete with oxygen, HIF-α subunits are unstable,
Evidence for HIF activation in cancer
Initial analyses of regional gene expression within tumours provided indirect evidence for HIF activation by micro-environmental tumour hypoxia. Thus, expression of HIF-responsive genes or HRE-linked reporter genes was observed in peri-necrotic (presumed hypoxic) regions 19., 20.. Moreover, studies of experimental tumours derived from cells bearing inactivating mutations in one or other component of the HIF heterodimer indicated that this peri-necrotic pattern of gene expression is clearly
Mechanisms of HIF activation in cancer
Microenvironmental tumour hypoxia is undoubtedly an important mechanism of HIF activation in tumours. Nevertheless, recent studies in cell culture have demonstrated that other aspects of cancer enhance the activation of HIF by hypoxia, or activate HIF by oxygen-independent mechanisms.
These studies have demonstrated activation of HIF in response to inactivation of a number of different tumour suppressor genes, in response to activation of several different oncogenes, and in response to
Implications of activating an extensive physiological pathway in tumour development
How do these findings fit with genetic models regarding the multi-step evolution of cancer, in which mutation and clonal selection result in progressive development of the cancer phenotype? In the simplest model, phenotypic properties of the cancer would all be accounted for directly by mutations that confer a survival advantage. If a genetic mutation affects the function of a physiological pathway with extensive ramifications, however, then many phenotypic properties would be acquired as an
Events upstream of HIF activation
As outlined above, HIF activation is commonly observed in association with oncogenic events. Interestingly, with the exception of loss of VHL function, these events only partially activate the HIF pathway; also, the recognised mechanisms of HIF activation are indirect, with no description (as yet) of direct mutational activation of a HIF molecule. This is somewhat unexpected for a pathway centrally involved in cancer evolution, and suggests that clonal selection does not (or cannot) strongly
Consequences of HIF activation
Studies of gene-expression patterns have yielded some unexpected findings that are most easily explained by the co-selection of pathways lying downstream of HIF. Several recent studies have used large-scale gene arrays to identify new target genes in the hypoxia pathway that are upregulated in specific cancers or in cultured cells bearing tumour suppressor mutations 14•., 50•., 51•.. Many identified genes have functions that are likely to promote tumour growth and/or contribute to the malignant
Conclusions
Studies of the HIF system have provided substantial new insights into tumour biology. However, the interface of an extensive and complex physiological pathway with tumour development complicates the understanding of cause and effect in the cancer phenotype. When activity of a pathway, or expression of an individual gene, is found to be commonly upregulated in cancer, this may suggest a role in cancer development but because of co-selection of physiologically linked pathways this does not
Acknowledgements
Work in the authors’ laboratory is principally funded by the Wellcome Trust and the Medical Research Council.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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