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Review
. 2015 May 15;16(5):11055-86.
doi: 10.3390/ijms160511055.

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Calvin R Justus  1   2 , Edward J Sanderlin  3   4 , Li V Yang  5   6   7   8
Affiliations
Review

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

Calvin R Justus et al. Int J Mol Sci. .

Abstract

Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the "Warburg effect", commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.

Keywords: acidosis; cancer cell metabolism; cancer therapy; hypoxia; tumor microenvironment.

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Figures

Figure 1
Figure 1
The complex interactions between cancer cell metabolism and the tumor microenvironment. Cancer cells exhibit increased glycolysis even in the presence of oxygen (Warburg effect) and under hypoxic conditions glycolysis may be further stimulated (shown in red). The stimulation of glycolysis increases proton production and facilitates proton efflux via an array of acid transporters such as MCT, NHE, and proton pumps, causing acidosis in the tumor microenvironment. Acidosis acts as a negative feedback signal by lessening glycolytic flux and facilitating mitochondrial respiration (shown in black). ASCT: Na+-dependent glutamine transporter; CA: carbonic anhydrase; GDH: glutamate dehydrogenase; GLUT: glucose transporter; GPCR: G-protein-coupled receptor; HIF: hypoxia inducible factor; LAT: Na+-independent glutamine transporter; LDH: lactate dehydrogenase; MCT: monocarboxylate transporter; NHE: sodium/hydrogen exchanger; PDG: phosphate-dependent glutaminase; PDH: pyruvate dehydrogenase; PFK: phosphofructokinase; TCA: tricarboxylic acid cycle.
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