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Hypoxia signalling in cancer and approaches to enforce tumour regression

Abstract

Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pHi) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pHi-control systems.

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Figure 1: VEGF-A and angiopoietin-2 are key angiogenic factors induced by hypoxia.
Figure 2: Oxygen sensors contribute to the destruction and inactivation of HIF-1α.
Figure 3: Working model of two sets of HIF-1-regulated genes.
Figure 4: Hypoxia meets the mTOR pathway.
Figure 5: Hypoxia-induced loss of E-cadherin through the lysyl oxidase–Snail activation pathway.
Figure 6: Intracellular-pH-regulating systems as potential anti-cancer targets.

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Acknowledgements

We thank all our laboratory members for their discussion and support, and particularly C. Brahimi-Horn for thoroughly reviewing and critically reading the manuscript. Because of space constraints, we apologize to the many research groups whose citations were omitted or cited indirectly. Financial support was from the Centre National de la Recherche Scientifique (CNRS), Centre A. Lacassagne, Ministère de l'Education, de la Recherche et de la Technologie, Ligue Nationale Contre le Cancer (Equipe labellisée), the GIP HMR (contract No. 1/9743B-A3) and Conseil Regional PACA.

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Pouysségur, J., Dayan, F. & Mazure, N. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006). https://doi.org/10.1038/nature04871

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