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Dysregulated pH: a perfect storm forcancer progression
Bradley A.Webb, Michael Chimenti, Matthew P.Jacobson and Diane L.Barber
Abstract | 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.
Invasive tumour cells acquire various adaptive characteristics, including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis and increased replicative potential1. Mutations that underlie these characteristics have been studied extensively. Although less recognized, dysregulated pH is also an adaptive feature of most cancers, regardless of their tissue origin or genetic background. In normal differentiated adult cells, intracellular pH (pHi) is generally ~7.2 and lower than the extracellular pH (pHe) of ~7.4. However, cancer cells have a higher pHi of >7.4 and a lower pHe of ~6.77.1 (REFS25). This reversed pH gradient creates a perfect storm for metastatic progression (FIG.1a) and, as suggested by recent evidence, may be permissive for some of the acquired characteristics of cancers. As we describe, an increased pHi
is permissive for cell proliferation and the evasion of apoptosis, facilitates metabolic adaptation and is obligatory for efficient directed cell migration. A decreased pHe
limits dynamic HCO3-dependent buffering, promotes extracellular matrix (ECM)
remodelling and stimulates acid-activated proteases to facilitate tumour cell invasion and dissemination.
The increased pHi of cancer cells is paradoxical considering that higher proliferative and glycolytic rates generate metabolic acids. However, changes in the expression and/or activity of plasma membrane ion pumps and transporters that facilitate H+
efflux maintain a higher pHi and lower pHe (FIG.1b). Most notable in cancers is the increased expression and/or activity of:
H+-ATPases68, the Na+H+ exchanger NHE1 of the SLC9A family912 and the monocarboxylateH+...