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

U2 - 10.1016/j.semcancer.2016.12.001

DO - 10.1016/j.semcancer.2016.12.001

M3 - Review

C2 - 28007556

AN - SCOPUS:85009168640

VL - 43

SP - 5

EP - 16

JO - Seminars in Cancer Biology

JF - Seminars in Cancer Biology

SN - 1044-579X

ER -