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Investigating hypoxic tumor physiology through gene expression patterns

Oncogene volume 22, pages 5907–5914 (2003)Cite this article

Abstract

Clinical evidence shows that tumor hypoxia is an independent prognostic indicator of poor patient outcome. Hypoxic tumors have altered physiologic processes, including increased regions of angiogenesis, increased local invasion, increased distant metastasis and altered apoptotic programs. Since hypoxia is a potent controller of gene expression, identifying hypoxia-regulated genes is a means to investigate the molecular response to hypoxic stress. Traditional experimental approaches have identified physiologic changes in hypoxic cells. Recent studies have identified hypoxia-responsive genes that may define the mechanism(s) underlying these physiologic changes. For example, the regulation of glycolytic genes by hypoxia can explain some characteristics of the Warburg effect. The converse of this logic is also true. By identifying new classes of hypoxia-regulated gene(s), we can infer the physiologic pressures that require the induction of these genes and their protein products. Furthermore, these physiologically driven hypoxic gene expression changes give us insight as to the poor outcome of patients with hypoxic tumors. Approximately 1–1.5% of the genome is transcriptionally responsive to hypoxia. However, there is significant heterogeneity in the transcriptional response to hypoxia between different cell types. Moreover, the coordinated change in the expression of families of genes supports the model of physiologic pressure leading to expression changes. Understanding the evolutionary pressure to develop a ‘hypoxic response’ provides a framework to investigate the biology of the hypoxic tumor microenvironment.

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Acknowledgements

This work was supported in part by Varian Biosynergy and NIH Grant CA67166. LF was supported by a predoctoral fellowship from Fondazione Italiana per la Ricerca sul Cancero.

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Authors and Affiliations

  1. Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, 94305, CA, USA

    Nicholas C Denko, Lucrezia A Fontana, Karen M Hudson, Patrick D Sutphin & Amato J Giaccia

  2. Department of Genetics, Stanford University School of Medicine, Stanford, 94305, CA, USA

    Soumya Raychaudhuri & Russ Altman

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  1. Nicholas C Denko
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  2. Lucrezia A Fontana
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Correspondence to Nicholas C Denko.

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Supplemental data is available at: http://cbrl.stanford.edu/hypoxia/welcome.htm

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Denko, N., Fontana, L., Hudson, K. et al. Investigating hypoxic tumor physiology through gene expression patterns. Oncogene 22, 5907–5914 (2003). https://doi.org/10.1038/sj.onc.1206703

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