Roles of pH and the Na+/H+ exchanger NHE1 in cancer: from cell biology and animal models to an emerging translational perspective?

Christian Stock; Stine Helene Falsig Pedersen

doi:10.1016/j.semcancer.2016.12.001

Roles of pH and the Na⁺/H⁺ exchanger NHE1 in cancer: from cell biology and animal models to an emerging translational perspective?

Christian Stock^*, Stine Helene Falsig Pedersen

^*Corresponding author for this work

Cell Biology and Physiology

52 Citations (Scopus)

Abstract

Acidosis is characteristic of the solid tumor microenvironment. Tumor cells, because they are highly proliferative and anabolic, have greatly elevated metabolic acid production. To sustain a normal cytosolic pH homeostasis they therefore need to either extrude excess protons or to neutralize them by importing HCO₃ ^-, in both cases causing extracellular acidification in the poorly perfused tissue microenvironment. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a ubiquitously expressed acid-extruding membrane transport protein, and upregulation of its expression and/or activity is commonly correlated with tumor malignancy. The present review discusses current evidence on how altered pH homeostasis, and in particular NHE1, contributes to tumor cell motility, invasion, proliferation, and growth and facilitates evasion of chemotherapeutic cell death. We summarize data from in vitro studies, 2D-, 3D- and organotypic cell culture, animal models and human tissue, which collectively point to pH-regulation in general, and NHE1 in particular, as potential targets in combination chemotherapy. Finally, we discuss the possible pitfalls, side effects and cellular escape mechanisms that need to be considered in the process of translating the plethora of basic research data into a clinical setting.

Original language	English
Journal	Seminars in Cancer Biology
Volume	43
Pages (from-to)	5-16
Number of pages	12
ISSN	1044-579X
DOIs	https://doi.org/10.1016/j.semcancer.2016.12.001
Publication status	Published - Apr 2017

Keywords

Acidosis
Chemotherapy
Invasiveness
Metabolism
Tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.semcancer.2016.12.001

Cite this

@article{6464937fa3404344a235d4a74daa3844,

title = "Roles of pH and the Na+/H+ exchanger NHE1 in cancer: from cell biology and animal models to an emerging translational perspective?",

abstract = "Acidosis is characteristic of the solid tumor microenvironment. Tumor cells, because they are highly proliferative and anabolic, have greatly elevated metabolic acid production. To sustain a normal cytosolic pH homeostasis they therefore need to either extrude excess protons or to neutralize them by importing HCO3 -, in both cases causing extracellular acidification in the poorly perfused tissue microenvironment. The Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed acid-extruding membrane transport protein, and upregulation of its expression and/or activity is commonly correlated with tumor malignancy. The present review discusses current evidence on how altered pH homeostasis, and in particular NHE1, contributes to tumor cell motility, invasion, proliferation, and growth and facilitates evasion of chemotherapeutic cell death. We summarize data from in vitro studies, 2D-, 3D- and organotypic cell culture, animal models and human tissue, which collectively point to pH-regulation in general, and NHE1 in particular, as potential targets in combination chemotherapy. Finally, we discuss the possible pitfalls, side effects and cellular escape mechanisms that need to be considered in the process of translating the plethora of basic research data into a clinical setting.",

keywords = "Acidosis, Chemotherapy, Invasiveness, Metabolism, Tumor microenvironment",

author = "Christian Stock and Pedersen, {Stine Helene Falsig}",

year = "2017",

month = apr,

doi = "10.1016/j.semcancer.2016.12.001",

language = "English",

volume = "43",

pages = "5--16",

journal = "Seminars in Cancer Biology",

issn = "1044-579X",

publisher = "Academic Press",

}

TY - JOUR

T1 - Roles of pH and the Na+/H+ exchanger NHE1 in cancer

T2 - from cell biology and animal models to an emerging translational perspective?

AU - Stock, Christian

AU - Pedersen, Stine Helene Falsig

PY - 2017/4

Y1 - 2017/4

N2 - Acidosis is characteristic of the solid tumor microenvironment. Tumor cells, because they are highly proliferative and anabolic, have greatly elevated metabolic acid production. To sustain a normal cytosolic pH homeostasis they therefore need to either extrude excess protons or to neutralize them by importing HCO3 -, in both cases causing extracellular acidification in the poorly perfused tissue microenvironment. The Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed acid-extruding membrane transport protein, and upregulation of its expression and/or activity is commonly correlated with tumor malignancy. The present review discusses current evidence on how altered pH homeostasis, and in particular NHE1, contributes to tumor cell motility, invasion, proliferation, and growth and facilitates evasion of chemotherapeutic cell death. We summarize data from in vitro studies, 2D-, 3D- and organotypic cell culture, animal models and human tissue, which collectively point to pH-regulation in general, and NHE1 in particular, as potential targets in combination chemotherapy. Finally, we discuss the possible pitfalls, side effects and cellular escape mechanisms that need to be considered in the process of translating the plethora of basic research data into a clinical setting.

AB - Acidosis is characteristic of the solid tumor microenvironment. Tumor cells, because they are highly proliferative and anabolic, have greatly elevated metabolic acid production. To sustain a normal cytosolic pH homeostasis they therefore need to either extrude excess protons or to neutralize them by importing HCO3 -, in both cases causing extracellular acidification in the poorly perfused tissue microenvironment. The Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed acid-extruding membrane transport protein, and upregulation of its expression and/or activity is commonly correlated with tumor malignancy. The present review discusses current evidence on how altered pH homeostasis, and in particular NHE1, contributes to tumor cell motility, invasion, proliferation, and growth and facilitates evasion of chemotherapeutic cell death. We summarize data from in vitro studies, 2D-, 3D- and organotypic cell culture, animal models and human tissue, which collectively point to pH-regulation in general, and NHE1 in particular, as potential targets in combination chemotherapy. Finally, we discuss the possible pitfalls, side effects and cellular escape mechanisms that need to be considered in the process of translating the plethora of basic research data into a clinical setting.

KW - Acidosis

KW - Chemotherapy

KW - Invasiveness

KW - Metabolism

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85009168640&partnerID=8YFLogxK

U2 - 10.1016/j.semcancer.2016.12.001

DO - 10.1016/j.semcancer.2016.12.001

M3 - Review

C2 - 28007556

AN - SCOPUS:85009168640

SN - 1044-579X

VL - 43

SP - 5

EP - 16

JO - Seminars in Cancer Biology

JF - Seminars in Cancer Biology

ER -