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
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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- "Enhanced glycolytic activity generates large amounts of acidic by-products, particularly lactic acid (DeBerardinis et al., 2007; Gatenby and Gillies, 2008; Lunt and Vander Heiden, 2011). This threatens the intracellular pH (pHi) homeostasis and consequently cell growth and survival, as alterations in pHi may disturb a wide range of biosynthetic and signalling processes (Gottlieb et al., 1996; Lagadic-Gossmann et al., 2004; Webb et al., 2011). Cancer cells have developed adaptive strategies to extrude acid and regulate pHi that will be further discussed below. "
ABSTRACT: In their quest for survival and successful growth, cancer cells optimize their cellular processes to enable them to outcompete normal cells in their microenvironment. In essence cancer cells: (i) enhance uptake of nutrients/metabolites, (ii) utilise nutrients more efficiently via metabolic alterations and (iii) deal with the metabolic waste products in a way that furthers their progression whilst hampering the survival of normal tissue. Hypoxia Inducible Factors (HIFs) act as essential drivers of these adaptations via the promotion of numerous membrane proteins including glucose transporters (GLUTs), monocarboxylate transporters (MCTs), amino-acid transporters (LAT1, xCT), and acid-base regulating carbonic anhydrases (CAs). In addition to a competitive growth advantage for tumour cells, these HIF-regulated proteins are implicated in metastasis, cancer 'stemness' and the immune response. Current research indicates that combined targeting of these HIF-regulated membrane proteins in tumour cells will provide promising therapeutic strategies in the future.
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- "It is well known that the tumor microenvironment has unique physiological characteristics such as acidic pH , hypoxia , and up-regulation of certain enzymes . 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)   . "
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.
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- "A recent meta-analysis in human tissues that included the analysis of DNA damage levels corroborated with prevailing notion that DNA damage correlates with ageing  . Cellular stresses in the form of hypoxia, dysregulated pH, and high osmolarity microenvironment, all seem to inflict genetic instability, in general and chromosomal instability, in particular   . Oxidative stress, when accumulated due to lack of quenching of free radicals by the cellular enzymes, results in inflicting DNA base modifications and their eventual conversion to DNA strand breaks upon replication. "
ABSTRACT: Chromosomal instability is defined as a state of numerical and/or structural chromosomal anomalies in cells. Numerous studies have documented the incidence of chromosomal instability, which acutely or chronically may lead to accelerated ageing (tissue-wide or even organismal), cancer or other genetic disorders. Potential mechanisms leading to the generation of chromosome-genome instability include erroneous/inefficient DNA repair, chromosome segregation defects, spindle assembly defects, DNA replication stress, telomere shortening/dysfunction - to name a few. Understanding the cellular and molecular mechanisms for chromosomal instability in various human cells and tissues will be useful in elucidating the cause for many age associated diseases including cancer. This approach holds a great promise for the cytogenetic assays not only for prognosis but also for diagnostic purposes in clinical settings. In this review, a multi-dimensional approach has been attempted to portray the complexity behind the incidence of chromosome-genome instability including evolutionary implications at the species level for some of the mechanisms of chromosomal instability.
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