Dysregulated pH: A perfect storm for cancer progression

Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, USA.
Nature Reviews Cancer (Impact Factor: 37.4). 08/2011; 11(9):671-7. DOI: 10.1038/nrc3110
Source: PubMed


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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    • "It is well known that the tumor microenvironment has unique physiological characteristics such as acidic pH [17], hypoxia [18], and up-regulation of certain enzymes [19]. In particular, the extracellular pH (pH e ) of solid tumors is more acidic (pH 6.5 to 6.8) than that of normal tissues because cancer cells rely heavily on glycolysis for energy consumption (rather than oxidative phosphorylation) to increase biosynthetic functions, leading to an increased rate of lactic acid production (also known as the Warburg effect) [20] [21] [22]. "
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    Journal of Controlled Release 09/2015; DOI:10.1016/j.jconrel.2015.08.050 · 7.71 Impact Factor
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    • "Cancer cells could effectively excrete intracellular acid into the surrounding environment to form an acidified tumor microenvironment, which promotes angiogenesis, facilitates tumor metastasis, suppresses the host immune system, and contributes to chemoresistance [16]. Thus, a novel practical strategy that regulates cancer cell pH could be an effective approach to induce cancer cell death [78]. Treatment with 400 µM GYY4137 (a slow-releasing H 2 S donor) for 5 days significantly increases "
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    Nitric Oxide 08/2015; 50. DOI:10.1016/j.niox.2015.08.004 · 3.52 Impact Factor
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    • "According to [5] [27], relatively high pH i fosters cell division and provides resistance to cell apoptosis. Hence (see [5]), higher pH i may cause a reentry of the cell into the mitotic phase or suppression of mitotic arrest. "
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    ABSTRACT: Cancer research is not only a fast growing field involving many branches of science, but also an intricate and diversified field rife with anomalies. One such anomaly is the consistent reliance of cancer cells on glucose metabolism for energy production even in a normoxic environment. Glycolysis is an inefficient pathway for energy production and normally is used during hypoxic conditions. Since cancer cells have a high demand for energy (e.g. for proliferation) it is somehow paradoxical for them to rely on such a mechanism. An emerging conjecture aiming to explain this behavior is that cancer cells preserve this aerobic glycolytic phenotype for its use in invasion and metastasis (see, e.g., Gatenby and Gillies (2004) [1], Racker (1976) [2]). We follow this hypothesis and propose a new model for cancer invasion, depending on the dynamics of extra- and intracellular protons, by building upon the existing ones. We incorporate random perturbations in the intracellular proton dynamics to account for uncertainties affecting the cellular machinery. Finally, we address the well-posedness of our setting and use numerical simulations to illustrate the model predictions.
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