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Tumor pH and metastasis: a malignant process beyond hypoxia

  • Oliver ThewsEmail author
  • Anne Riemann
Article
  • 216 Downloads

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.

Keywords

Tumor acidosis Mechanisms of metastasis Endothelial-to-mesenchymal transition Proton (H+) sensing mechanisms Intracellular signaling 

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

Notes

Funding information

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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Julius Bernstein Institute of PhysiologyUniversity of Halle-WittenbergHalle (Saale)Germany

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