Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies

Abstract

Metastasis is the leading cause of cancer-related deaths. Recent research has implicated tumor inflammation as a promoter of metastasis. Myeloid, lymphoid, and mesenchymal cells in the tumor microenvironment promote inflammatory signaling amongst each other and together with cancer cells to modulate sustained inflammation, which may enhance cancer invasiveness. Tumor hypoxia, a state of reduced available oxygen present in the majority of solid tumors, acts as a prognostic factor for a worse outcome and is known to have a role in tumor inflammation through the regulation of inflammatory mediator signals in both cancer and neighboring cells in the microenvironment. Multiple methods to target tumor hypoxia have been developed and tested in clinical trials, and still more are emerging as the impacts of hypoxia become better understood. These strategies include mechanistic inhibition of the hypoxia inducible factor signaling pathway and hypoxia activated pro-drugs, leading to both anti-tumor and anti-inflammatory effects. This prompts a need for further research on the prevention of hypoxia-mediated inflammation in cancer. Hypoxia-targeting strategies seem to have the most potential for therapeutic benefit when combined with traditional chemotherapy agents. This paper will serve to summarize the role of the inflammatory response in metastasis, to discuss how hypoxia can enable or enhance inflammatory signaling, and to review established and emerging strategies to target the hypoxia-inflammation-metastasis axis.

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Acknowledgments

We acknowledge the researchers who work in the field of hypoxia, inflammation, and metastasis, and apologize for any work that was not cited due to space constraints.

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Correspondence to Daniele M. Gilkes.

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Funding

Work in the author’s lab is supported by the NCI (R00-CA181352 and U54-CA210173), Susan G. Komen Foundation (CCR17483484), and pilot funds from The Breast Cancer Research Foundation and The JKTG foundation. D.M. Gilkes is a 2016 V Scholar awardee (V2016–024).

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The authors declare no conflict of interest.

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DiGiacomo, J.W., Gilkes, D.M. Tumor Hypoxia As an Enhancer of Inflammation-Mediated Metastasis: Emerging Therapeutic Strategies. Targ Oncol 13, 157–173 (2018). https://doi.org/10.1007/s11523-018-0555-4

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