Targeting lactate metabolism for cancer therapeutics
Joanne R. Doherty, John L. Cleveland
Joanne R. Doherty, John L. Cleveland
Published September 3, 2013
Citation Information: J Clin Invest. 2013;123(9):3685-3692. https://doi.org/10.1172/JCI69741.
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Targeting lactate metabolism for cancer therapeutics

Abstract

Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non–tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.

Authors

Joanne R. Doherty, John L. Cleveland

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Figure 3

Three models of lactate shuttling in cancer.

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Three models of lactate shuttling in cancer. (A) The reverse Warburg eff...
(A) The reverse Warburg effect occurs when cancer cells secrete hydrogen peroxide, which is thought to generate a pseudo-hypoxic environment in the stroma. In turn, this induces HIF-1α, MCT4 expression, and glycolysis in stromal fibroblasts, which then efflux excess lactate via MCT4. Stromal-derived lactate is then imported by tumor cells via MCT1 and used as an oxidative metabolite. (B) In metabolic symbiosis, tumor cells in hypoxic regions of the tumor efflux lactate through MCT4, which is then imported by tumor cells in less hypoxic regions via MCT1 and used as an oxidative metabolite. This shuttling facilitates delivery of glucose to the hypoxic regions of the tumor. (C) In the vascular endothelial lactate shuttle, tumor cells efflux lactate via MCT4, which is imported by vascular endothelial cells by MCT1. Lactate is then converted to pyruvate, which activates HIF-1α and NF-κB/IL-8 signaling.