Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Abstract

Major changes in intra- and extracellular pH homoeostasis are shared features of most solid tumours. These changes stem in large part from the metabolic shift of most cancer cells towards glycolytic metabolism and other processes associated with net acid production. In combination with oncogenic signalling and impact from factors in the tumour microenvironment, this upregulates acid-extruding plasma membrane transport proteins which maintain intracellular pH normal or even more alkaline compared with that of normal cells, while in turn acidifying the external microenvironment. Mounting evidence strongly indicates that this contributes significantly to cancer development by favouring e.g. cancer cell migration, invasion and chemotherapy resistance. Finally, while still under-explored, it seems likely that non-cancer cells in the tumour microenvironment also exhibit altered pH regulation and that this may contribute to their malignant properties. Thus, the physical tumour microenvironment and the cancer and stromal cells within it undergo important reciprocal interactions which modulate the tumour pH profile, in turn severely impacting on the course of cancer progression. Here, we summarize recent knowledge of tumour metabolism and the tumour microenvironment, placing it in the context of tumour pH regulation, and discuss how interfering with these properties may be exploited clinically.

Keywords: glycolysis; hypoxia; metabolism; pH-regulation; tumour stroma.

Figure 1.

Major metabolic pathways in tumour cells. The figure illustrates the major metabolic pathways in which changes are known to occur in cancer. See text for details. α-KG, α-ketoglutarate; ACLY, ATP citrate lyase; GLS, glutaminase; GSH, glutathione; HK, hexokinase; IDH2, isocitrate dehydrogenase; LDH, lactate dehydrogenase; PFK, phosphofructokinase; TCA, tricarboxylic acid; ess AA, essential amino acids; PPP, pentose phosphate pathway; (R)-2HG, (R)-2-hydroxyglutarate.

Figure 2.

Reciprocal interactions between cancer cells and the surrounding stromal cells. A tumour generally comprises multiple different cell types that interact reciprocally and heterotypically. Reciprocal signalling events between the cancer cells and the surrounding stromal cells cause progression towards more aggressive phenotypes. The figure illustrates only a selection of the central secreted factors within the TME. See text for details. CSF-1, colony-stimulating factor-1; EGF, epidermal growth factor; (b)FGF, (basic) fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IL-1/6, interleukin-1/6; MCP, monocyte chemotactic protein; MMPs, matrix metalloproteases; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor.