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Intermittent hypoxia induces a metastatic phenotype in breast cancer

Oncogene volume 37, pages 4214–4225 (2018)Cite this article

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Abstract

Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor-supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal diversity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth.

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Acknowledgements

The authors thank Carmen Yong for help with flow cytometry and IV injections, and the groups of POH and AM for proof-reading the manuscript. This work was supported by funding from a project grant from the National Health and Medical Research Council of Australia (APP1068510 to AM). POH was supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia (APP1079133). AM was supported by Cancer Council Queensland (APP1045620), and National Breast Cancer Foundation (Australia) fellowship and grant (ECF-11-09, NC-13-26). AC was supported by an APA scholarship.

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Author notes

  1. Jaclyn Sceneay

    Present address: Brigham & Women’s Hospital, Boston, MA, 02115, USA

Authors and Affiliations

  1. Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, VIC, 3002, Australia

    Anna Chen, Nathan Gödde, Tanja Kinwel & Patrick O Humbert

  2. Department of Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia

    Anna Chen, Tanja Kinwel & Patrick O Humbert

  3. Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, 4006, Australia

    Anna Chen, Jaclyn Sceneay, Sunyoung Ham & Andreas Möller

  4. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia

    Nathan Gödde, Tanja Kinwel & Patrick O Humbert

  5. Sir Peter MaCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia

    Nathan Gödde & Patrick O Humbert

  6. Pathology and Pathogenesis Group, Diagnostics Surveillance & Response, Australian Animal Health Laboratory, CSIRO, Geelong, VIC, 3220, Australia

    Nathan Gödde

  7. Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Brisbane, QLD, 4000, Australia

    Erik W Thompson

  8. Department of Surgery, The University of Melbourne, St. Vincent’s Hospital, East Melbourne, 3002, Australia

    Erik W Thompson

  9. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, 3010, Australia

    Patrick O Humbert

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Chen, A., Sceneay, J., Gödde, N. et al. Intermittent hypoxia induces a metastatic phenotype in breast cancer. Oncogene 37, 4214–4225 (2018). https://doi.org/10.1038/s41388-018-0259-3

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