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Protons make tumor cells move like clockwork

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Abstract

Cancer accounts for 13% of the yearly total mortality worldwide. Most cancer deaths are the sequel of metastatic diseases rather than of primary tumor growth. Thus, the major challenge in tumor therapy is the tumor cells’ ability to metastasize. The extent to which a tumor metastasizes correlates with the tumor cells’ migratory activity. Tumor cell migration requires a coordinated formation and release of cell adhesion contacts, a controlled cytoskeletal dynamics, the digestion and reorganization of the extracellular matrix, and local ion and water transport across the plasma membrane. All of these operations depend on intracellular pH (pHi) and extracellular pH (pHe). Numerous H+, HCO −3 , and monocarboxylate transporters as well as different carbonic anhydrase isozymes have considerable impact on pHi and pHe which spotlights them as possible, potential targets for anticancer therapeutics. Especially in solid tumors whose vascularization is often not sufficient, tumor cells cope with hypoxia and the resulting glycolysis by overexpressing the Na+/H+ exchanger NHE1, monocarboxylate transporters MCT1 and/or MCT4, and the carbonic anhydrase CA IX. NHE1, MCT, and CA IX activity lead to an acidification of the extracellular space in order to maintain the cytosolic pH homeostasis stable. The present article gives a review on how this characteristic, acidic tumor micro- and nanoenvironment controls tumor cell migration.

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Acknowledgments

Research performed in our laboratory was supported by the Deutsche Forschungsgemeinschaft (DFG), by the fund “Innovative Medical Research” of the University of Münster Medical School (Grant number: ST 2 1 06 01), by the Rolf Dierichs-Stiftung (CS), and by the IZKF (Interdiszplinäres Zentrum für Klinische Forschung) at Münster University (Schw2/030/08).

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  1. Institut für Physiologie II, University of Münster, Robert-Koch-Str. 27b, 48149, Münster, Germany

    Christian Stock & Albrecht Schwab

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Correspondence to Christian Stock.

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Stock, C., Schwab, A. Protons make tumor cells move like clockwork. Pflugers Arch - Eur J Physiol 458, 981–992 (2009). https://doi.org/10.1007/s00424-009-0677-8

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