bims-stacyt 2019-11-24 papers

Front Oncol. 2019 ;9 1143

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches.

Karen G de la Cruz-López, Leonardo Josué Castro-Muñoz, Diego O Reyes-Hernández, Alejandro García-Carrancá, Joaquín Manzo-Merino.

Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as "Warburg effect or aerobic glycolysis." As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

Keywords: acidification; immune response; lactate; therapy; tumor microenvironment (TME)

DOI: https://doi.org/10.3389/fonc.2019.01143

Trends Cancer. 2019 Nov;pii: S2405-8033(19)30184-0. [Epub ahead of print]5(11): 656-658

Metabolic Stress Triggers Immune Escape by Tumors.

Joana B Nunes, Bart Everts.

There is major interest in understanding the role of the tumor microenvironment in immune escape. In a recent report, Marijt et al. shed light on the signaling cascade that leads to decreased surface expression of MHC class I by tumor cells triggered by low oxygen and glucose availability, revealing new opportunities for therapeutic intervention.

Keywords: PI3K; immune escape; metabolism; tumor microenvironment

DOI: https://doi.org/10.1016/j.trecan.2019.09.001

Mol Cell. 2019 Nov 05. pii: S1097-2765(19)30801-9. [Epub ahead of print]

Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Jing-Yiing Wu, Tsai-Wang Huang, Yi-Ting Hsieh, Yi-Fu Wang, Chia-Chien Yen, Guan-Lin Lee, Chang-Ching Yeh, Yi-Jen Peng, Ya-Yi Kuo, Hsiu-Ting Wen, Hui-Chen Lin, Cheng-Wen Hsiao, Kenneth K Wu, Hsing-Jien Kung, Yu-Juei Hsu, Cheng-Chin Kuo.

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

Keywords: PI3K-HIF-1α axis; SUCNR1; cancer metastasis; metabolomics; succinate; tumor microenvironment; tumor-associated macrophages

DOI: https://doi.org/10.1016/j.molcel.2019.10.023