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The growing complexity of HIF-1α’s role in tumorigenesis: DNA repair and beyond

Oncogene volume 32, pages 3569–3576 (2013)Cite this article

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Abstract

Lack of oxygen (hypoxia) is a central hallmark of cancer and a pivotal driving force of malignant progression. Transcriptional activators of the hypoxia-inducible factor α (HIFα) family represent the principal molecular mediators of hypoxia under both physiological and pathophysiological conditions. While HIF-2α is expressed in a tissue- and cell-type-restricted manner, stabilization of HIF-1α was reported in tumours of widely different origin, and functional analyses led to the perception of HIF-1α as an oncoprotein. In this review, we aim to acknowledge HIFα’s growing complexity by outlining its functional relevance for genomic integrity and tumour heterogeneity, two features of paramount importance for basic and clinical oncology. Pharmaceutical companies around the globe are ambitiously hunting for HIF-1α-inhibiting compounds, some of which are currently being evaluated in phase 1 trials. To avoid the rather disappointing clinical efficacy emblematic of most targeted therapeutics, potential resistance mechanisms of, as well as potential combination partners for, HIF-1α-inhibiting drugs should be evaluated. In this regard, the interrelation of HIF-1α with genomic integrity and tumour heterogeneity offers ample possibilities, potentially resulting in more efficient clinical translation of HIF-1α’s pathobiology.

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Acknowledgements

Research in the Cramer laboratory is supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Bildung und Forschung and (in collaboration) Cancer Research United Kingdom. Stefan Kempa received funding by the Bundesministerium für Bildung und Forschung and the Senate of Berlin. We thank the members of our laboratories and our collaborators for helpful discussions.

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Authors and Affiliations

  1. Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Berlin, Germany

    N Rohwer & T Cramer

  2. Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    C Zasada & S Kempa

  3. Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany

    T Cramer

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  1. N Rohwer
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  2. C Zasada
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  3. S Kempa
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  4. T Cramer
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Correspondence to T Cramer.

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Rohwer, N., Zasada, C., Kempa, S. et al. The growing complexity of HIF-1α’s role in tumorigenesis: DNA repair and beyond. Oncogene 32, 3569–3576 (2013). https://doi.org/10.1038/onc.2012.510

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  • DOI: https://doi.org/10.1038/onc.2012.510

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