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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    ABSTRACT: One of the most challenging and clinically important goals in nanomedicine is to deliver imaging and therapeutic agents to solid tumors. Here we discuss the recent design and development of stimuli-responsive smart nanoparticles for targeting the common attributes of solid tumors such as their acidic and hypoxic microenvironments. This class of stimuli-responsive nanoparticles is inactive during blood circulation and under normal physiological conditions, but is activated by acidic pH, enzymatic up-regulation, or hypoxia once they extravasate into the tumor microenvironment. The nanoparticles are often designed to first "navigate" the body's vascular system, "dock" at the tumor sites, and then "activate" for action inside the tumor interstitial space. They combine the favorable biodistribution and pharmacokinetic properties of nanodelivery vehicles and the rapid diffusion and penetration properties of smaller drug cargos. By targeting the broad tumor habitats rather than tumor-specific receptors, this strategy has the potential to overcome the tumor heterogeneity problem and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 09/2015; 219. DOI:10.1016/j.jconrel.2015.08.050 · 7.71 Impact Factor
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    • "This metabolic phenotype has been studied by noninvasive techniques, such as 18 F-fluorodeoxyglucose positron emission tomography and magnetic resonance spectroscopy (MRS of 13 C-labeled substrates) [12] [13]. Due to enhanced glycolysis, tumor cells synthesize high levels of lactate and export H + , resulting in acidification of the microenvironment, which in turn promotes invasion and dissemination [14] [15]. Recent studies with two isogenic murine breast cancer cell lines derived from the same spontaneous breast tumor, 4T1 and 67NR [16], have shown differences in lactate dehydrogenase (LDH) A expression during normoxia and hypoxia [17]. "
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    ABSTRACT: Cancer cells adapt their metabolism during tumorigenesis. We studied two isogenic breast cancer cells lines (highly metastatic 4T1; nonmetastatic 67NR) to identify differences in their glucose and glutamine metabolism in response to metabolic and environmental stress. Dynamic magnetic resonance spectroscopy of 13C-isotopomers showed that 4T1 cells have higher glycolytic and tricarboxylic acid (TCA) cycle flux than 67NR cells and readily switch between glycolysis and oxidative phosphorylation (OXPHOS) in response to different extracellular environments. OXPHOS activity increased with metastatic potential in isogenic cell lines derived from the same primary breast cancer: 4T1 > 4T07 and 168FARN (local micrometastasis only) > 67NR. We observed a restricted TCA cycle flux at the succinate dehydrogenase step in 67NR cells (but not in 4T1 cells), leading to succinate accumulation and hindering OXPHOS. In the four isogenic cell lines, environmental stresses modulated succinate dehydrogenase subunit A expression according to metastatic potential. Moreover, glucose-derived lactate production was more glutamine dependent in cell lines with higher metastatic potential. These studies show clear differences in TCA cycle metabolism between 4T1 and 67NR breast cancer cells. They indicate that metastases-forming 4T1 cells are more adept at adjusting their metabolism in response to environmental stress than isogenic, nonmetastatic 67NR cells. We suggest that the metabolic plasticity and adaptability are more important to the metastatic breast cancer phenotype than rapid cell proliferation alone, which could 1) provide a new biomarker for early detection of this phenotype, possibly at the time of diagnosis, and 2) lead to new treatment strategies of metastatic breast cancer by targeting mitochondrial metabolism. Full article:
    Neoplasia (New York, N.Y.) 08/2015; 17(8):671-684. DOI:10.1016/j.neo.2015.08.005 · 4.25 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.
    Nonlinear Analysis Real World Applications 04/2015; 22:176–205. DOI:10.1016/j.nonrwa.2014.08.008 · 2.52 Impact Factor
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