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Review
. 2017 Oct:48:47-53.
doi: 10.1016/j.ceb.2017.05.006. Epub 2017 Jun 9.

Metabolism shapes the tumor microenvironment

Miguel Reina-Campos  1 , Jorge Moscat  2 , Maria Diaz-Meco  3
Affiliations
Review

Metabolism shapes the tumor microenvironment

Miguel Reina-Campos et al. Curr Opin Cell Biol. 2017 Oct.

Abstract

Tumors are strongly influenced by the surrounding normal tissue, which forms a specialized niche termed the tumor microenvironment (TME). The TME is modeled by cancer cells for their own benefit through a complex array of interactions. The identification of new forms of communication within the TME, which are dependent on the tumor's metabolic activity, has expanded our understanding of this heterocellular regulation and has revealed potential therapeutic targets. This review will summarize recent findings on the metabolic regulation of tumor cells by the TME. The concepts to be discussed include the existence of metabolic intratumoral heterogeneity, the contribution of cancer associated fibroblasts (CAFs) to tumor progression, and the regulation of tumor immunology by tumor-secreted metabolites.

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Figures

Figure 1
Figure 1. Tumor Metabolic Heterogeneity
(A) Differential tumor vasculature perfusion promotes different carbon source usage in NSCLC. Low perfused areas use mainly glucose while highly perfused areas use other sources. (B) Oncogenic KRasG12D mutation load dictates a metabolic switch to an increased TCA-supported metabolism and augmented glutathione biosynthesis that increases the ROS-detoxifying ability.
Figure 2
Figure 2
Activated CAFs and PSCs maintain tumor growth by supplying free amino acids. Activated CAFs and PSCs mobilize free aminoacids by increasing glutamine biosynthesis and autophagy, respectively. Free aminoacids are fed to the tumor to sustain its metabolic demands of Non-Essential Amino Acids (NEAA), lipids and nucleotides. Also, oncogenic KRasG12D is able to extent cell-autonomous signaling by hijacking CAFs metabolism to obtain reciprocal signaling and support tumor growth, survival and metabolism.
Figure 3
Figure 3. Opposed and cell-dependent role of p62 in tumor epithelia vs stromal CAFs and HSCs
(A) Amino acids (AAs) can activate mTORC1 in a p62-dependent manner in Prostate Cancer (PCa) epithelial cells, which promotes anabolism and cell growth and blocks autophagy. Autophagy inhibition leads to accumulation of p62 and further mTORC1 activation. In the CAF compartment, p62 is downregulated, which negatively affects mTORC1 and c-Myc’s ability to sustain adequate metabolic detoxification, which leads to elevation of ROS and paracrine and autocrine signaling by IL6 and TGFβ. (B) In the liver, accumulation of p62 leads to increased NRF2 and NFκB transcriptional activation that in turns mediates redox resistance and supports HCC development. Also, p62 promotes mTORC1 and c-Myc activity which sustains proliferation and metabolism conducive to HCC. In the stromal compartment, HSC activation leads to lower p62 levels, which prevent adequate VDR-RXR heterodimer formation and anti-fibrotic effects of Vitamin D.
Figure 4
Figure 4. Tumor metabolic activity exerts immunosuppressive functions
Low oxygen, nutritional competition and altered tumor metabolism induce an immunosuppressed TME. Accumulation of LDHA-derived lactate inhibits NK and T cell function, while polarizing macrophages into an M2 state that secretes Arginase 1 to the tumor. Also, low levels of arginine prevent memory-like T cell formation while low levels of glutamine induce an epigenetic rearrangement in tumor cells that lead to immune evasion.
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