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Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not?

Abstract

All human cells, including cancer cells, need oxygen and nutrients to survive. A widely used strategy to combat cancer is therefore the starvation of tumor cells by cutting off the blood supply of tumors. Clinical experience indeed shows that tumor progression can be delayed by anti-angiogenic agents. However, emerging evidence indicates that in certain experimental conditions, hypoxia as a result of pruning of the tumor microvasculature can promote tumor invasion and metastasis, although these findings are contextual and debated. Genetic studies in mice unveiled that vascular-targeting strategies that avoid aggravation of tumor hypoxia or even promote tumor oxygenation might prevent such an invasive metastatic switch. In this article, we will discuss the emerging link between hypoxia signaling and the various steps of metastasis.

Key Points

  • Hypoxia signaling through hypoxia-inducible factors, whose activity is regulated by oxygen sensing prolyl hydroxylases, controls tumor invasiveness and metastasis

  • Hypoxia signaling regulates the epithelial–mesenchymal transition, invasion, intravasation, survival of circulating tumor cells, extravasation, formation of the premetastatic niche, and growth from micrometastais to macrometastasis

  • Anti-angiogenic therapy with VEGF (receptor) inhibitors can aggravate hypoxia, but whether such therapy promotes tumor invasiveness and metastasis remains debated

  • The repair of the abnormal structure and function of tumor vessels through 'sustained vessel normalization' improves oxygen supply, reduces metastasis, and might offer novel therapeutic opportunities

  • Combining anti-angiogenic with anti-metastatic therapies might improve overall efficacy of anti-cancer treatment

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Figure 1: Schematic representation of the metastatic cascade and its regulation by hypoxia.
Figure 2: Effects of tumor vessel normalization on metastasis.

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Acknowledgements

K. De Bock is supported by the Fund for Scientific Research in Flanders (FWO). P. Carmeliet is supported by long-term structural funding (Methusalem funding by the Flemish Government), Interuniversity attraction pole (Grant P60/30, funded by the Belgian Government, BELSPO), FWO G.0532.10 and G.0651.08 (Flemish Government), and research grants by the Belgian Foundation against Cancer, the Susan G. Komen Breast Cancer Foundation, Leducq Network of Excellence, and Stichting Emmanuel van der Schueren (Belgium).

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All authors were involved in the research of data and the writing of the article, and provided substantial contributions to the discussion of content. P. Carmeliet reviewed/edited the manuscript before submission.

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Correspondence to Peter Carmeliet.

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P. Carmeliet worked as a consultant for Roche and Thrombogenics and is on the speakers bureau (honoraria) for Roche. He is patent holder/applicant and stockholder/director of Thrombogenics, from which he also received grant/research support. The other authors declare no competing interests.

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De Bock, K., Mazzone, M. & Carmeliet, P. Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not?. Nat Rev Clin Oncol 8, 393–404 (2011). https://doi.org/10.1038/nrclinonc.2011.83

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