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Tumor pH and metastasis: a malignant process beyond hypoxia

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A Correction to this article was published on 15 June 2019

This article has been updated

Abstract

Tumors often show, compared to normal tissues, a markedly decreased extracellular pH resulting from anaerobic or aerobic glycolysis in combination with a reduced removal of acidic metabolites. Several studies indicate that acidosis induces (independently from hypoxia) hematogenous and lymphatic spread of tumor cells worsening the long-term prognosis of tumor patients. This review gives an overview on the impact of low pH on different steps of metastasis including (a) local tumor cell invasion and angiogenesis, (b) intravasation of tumor cells and detachment into the circulation, and (c) adherence of circulating tumor cells, transmigration and invasion in the new host tissue. The review describes pH-dependent cellular mechanisms fostering these steps such as endothelial-to-mesenchymal transition (EMT), activation of cell migration, degradation of the extracellular matrix, or angiogenesis. The review discusses mechanisms of tumor cells for proton sensing including acid-sensitive ion channels (ASICs, TRPs) or ion transporters (NHE1) and G protein coupled H+-sensors. Finally, the review describes several intracellular signaling cascades activated by H+ sensing mechanisms leading to transcriptional, post-transcriptional, or functional changes in the cell relevant for the metastatic spread. From these studies, different therapeutical approaches are described to overcome tumor acidosis or to interfere with the signaling cascades to reduce the metastatic potential of tumors.

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Change history

  • 27 June 2019

    The authors have noticed a typographical error in the published article. The term “epithelial-to-mesenchymal transition” should have been used instead of the term “endothelial-to-mesenchymal transition” throughout the manuscript.

Abbreviations

CREB:

cAMP response element-binding protein

ASIC:

Acid-sensing ion channel

EMT:

Endothelial-to-mesenchymal transition

GPR:

G protein-coupled receptor

HIF:

Hypoxia-inducible factor

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix-metalloproteinase

TRP:

Transient receptor potential channel

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This study was supported by the Deutsche Forschungsgemeinschaft DFG (grant TH 482/6-1).

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  1. Julius Bernstein Institute of Physiology, University of Halle-Wittenberg, Magdeburger Str. 6, 06112, Halle (Saale), Germany

    Oliver Thews & Anne Riemann

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Thews, O., Riemann, A. Tumor pH and metastasis: a malignant process beyond hypoxia. Cancer Metastasis Rev 38, 113–129 (2019). https://doi.org/10.1007/s10555-018-09777-y

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