Although cancer is a diverse set of diseases, cancer cells share a number of adaptive hallmarks. Dysregulated pH is emerging as a hallmark of cancer because cancers show a 'reversed' pH gradient with a constitutively increased intracellular pH that is higher than the extracellular pH. This gradient enables cancer progression by promoting proliferation, the evasion of apoptosis, metabolic adaptation, migration and invasion. Several new advances, including an increased understanding of pH sensors, have provided insight into the molecular basis for pH-dependent cell behaviours that are relevant to cancer cell biology. We highlight the central role of pH sensors in cancer cell adaptations and suggest how dysregulated pH could be exploited to develop cancer-specific therapeutics.
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We thank T. Wittmann, S. Oakes and members of the Barber laboratory for helpful suggestions; K. Van Vliet for sharing data on pH-dependent conformational changes in integrin αvβ3; and C. Smith (University of California, San Francisco, USA) for computations on the pH-dependence of PFK1. Work on the structure and function of actin-binding pH sensors was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship to B.A.W. and a US National Institutes of Health grant, GM58642, to D.L.B.
M.P.J. is a consultant to Schrödinger LLC. The other authors declare no competing financial interests.
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Webb, B., Chimenti, M., Jacobson, M. et al. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11, 671–677 (2011). https://doi.org/10.1038/nrc3110
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