In many patients with NSCLC, lactate is a major fuel source for the tumor TCA cycle.
Major finding: In many patients with NSCLC, lactate is a major fuel source for the tumor TCA cycle.
Mechanism: Monocarboxylate transporters including MCT1 facilitate lactate uptake from the circulation in NSCLC.
Impact: The use of lactate as a fuel expands the nutrients used to produce energy in NSCLC.
In vitro, cancer cells utilize glucose and secrete lactate, and, in vivo, non–small cell lung cancers (NSCLC) have been shown to oxidize glucose in the tricarboxylic acid (TCA) cycle. It has been suggested that some tumors may also use lactate as fuel, although this has not been demonstrated in vivo. Using intraoperative infusion of 13C-labeled nutrients and postsurgical analysis of metabolic, molecular, and histologic features of tumors and adjacent lung tissue, Faubert and colleagues characterized tumors from 35 patients. The tumors exhibited heterogeneous 13C labeling between NSCLC tumors and within individual tumors. Many tumors with high 18flurodeoxyglucose uptake also consume lactate from the circulation. In subcutaneous and orthotopic NSCLC xenograft models, the tumors also took up lactate from the circulation and used it as fuel for the TCA cycle, and this lactate uptake required the monocarboxylate transporter MCT1 in vivo. Further, coinfusion of [U-13C]glucose and [3-13C]lactate revealed preferential use of lactate over glucose as a carbon source for the TCA cycle in NSCLC. Taken together, these findings demonstrate that lactate metabolism fuels the TCA cycle in lung tumors in vivo, and that lactate may be one of the most prominent respiratory fuels in NSCLC. Moreover, the concurrent use of multiple fuels in NSCLC may broaden the palette of PET probes and therapeutic targets in patients with NSCLC.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.