Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
Pierre Sonveaux, … , Olivier Feron, Mark W. Dewhirst
Pierre Sonveaux, … , Olivier Feron, Mark W. Dewhirst
Published November 20, 2008
Citation Information: J Clin Invest. 2008;118(12):3930-3942. https://doi.org/10.1172/JCI36843.
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Research Article

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice

Abstract

Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.

Authors

Pierre Sonveaux, Frédérique Végran, Thies Schroeder, Melanie C. Wergin, Julien Verrax, Zahid N. Rabbani, Christophe J. De Saedeleer, Kelly M. Kennedy, Caroline Diepart, Bénédicte F. Jordan, Michael J. Kelley, Bernard Gallez, Miriam L. Wahl, Olivier Feron, Mark W. Dewhirst

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Figure 6

MCT1 inhibition delays tumor growth, induces tumor core necrosis, and decreases tumor hypoxia.

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Metabolic characterization of oxidative SiHa and glycolytic WiDr tumor c...
(A) MCT1 is expressed at the plasma membrane of mouse LLc cells. Representative pictures show fluorescent staining of MCT1 (red) and nuclei (blue) in cultured cells. (B) From day 0, LLc tumor growth was determined in groups of mice treated with daily CHC (25 μmol in 200 μl i.p.) or vehicle. n = 11–17. (C) Representative H&E staining of biopsies of size-matched tumors after treatments. Dashed lines delineate necrosis (n). (D) MCT1 is not expressed at the plasma membrane of mouse TLT cells. Representative pictures show fluorescent staining of MCT1 (red) and nuclei (blue) in cultured cells. (E) Similar analysis was performed as in B, but using TLT cells. n = 6. (F) Similar analysis was performed as in A, but using WiDr human colorectal adenocarcinoma cells. (G) Similar analysis was performed as in B, but using WiDr cells in athymic Balb/C mice. n = 9–15. (H) Representative histological pictures of pimonidazole staining of WiDr tumor biopsies at the end of the tumor growth delay assay are shown with H&E counterstaining. Top: Analysis of whole tumor sections revealed extensive necrosis at the core of tumors from an animal treated with the MCT1 inhibitor. Bottom: MCT1 inhibition decreased tumor hypoxia around arterioles and at the tumor-muscle interface at the tumor periphery. Scale bars: 20 μm (A, D, and F); 200 μm (C and H). Error bars represent SEM.