Tumour microenvironment factors shaping the cancer metabolism landscape

Abstract

Cancer cells exhibit metabolic alterations that distinguish them from healthy tissues and make their metabolic processes susceptible to pharmacological targeting. Although typical cell-autonomous features of cancer metabolism have been emerging, it is increasingly appreciated that extrinsic factors also influence the metabolic properties of tumours. This review highlights evidence from the recent literature to discuss how conditions within the tumour microenvironment shape the metabolic character of tumours.

Figure 1

Overview of pathways implicated in cancer metabolism. Key enzymes are shown in white boxes. See text for details. Coloured block arrows denote contribution of metabolites to the respective cellular processes. ΔΨ_m denotes mitochondrial inner membrane potential. -CH₃ and -COCH₃ denote methyl and acetyl groups, respectively. ALT, alanine aminotransferase; 1,3-BG, 1,3-bisphosphoglycerate; DHAP, dihydroxyacetone phosphate; F-1,6-BP, fructose-1, 6-bisphosphate; F-6-P, fructose-6-phosphate; FH, fumarate hydratase; G-3-P, glyceraldehyde-3-phosphate; G-6-P, glucose-6-phosphate; GLS, glutaminase, GS, glutamine synthetase; α-KG, α-ketoglutarate; HK, hexokinase; IDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; OXPHOS, oxidative phosphorylation; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PFK, phosphofructokinase; PKM, pyruvate kinase M isoform; PEP, phosphoenolpyruvate; 2-PG, 2-phosphoglycerate; 3-PG, 3-phosphoglycerate; ROS, reactive oxygen species; SDH, succinate dehydrogenase.

Figure 2

Overview of key metabolic pathways implicated in the response of cancer cells to low oxygen conditions. See text for details. ACSS2, Acetyl-CoA synthase isoform 2; HIF, hypoxia-inducible factor; FFAs, free fatty acids; other abbreviations are as in Figure 1.

Figure 3

Paradigms of cancer–immune cell interactions. (A) Tryptophan metabolism yields the intermediate kynurenine, which promotes glioblastoma development by activating the aryl hydrocarbon receptor, a transcription factor that controls the expression of pro-tumorigenic genes. A downstream product of further kynurenine catabolism is NAD, which, among others, is an essential co-factor for the DNA repair enzyme poly-ADP ribose polymerase (PARP). Suppression of NAD synthesis by oncogenic signalling in liver tumours leads to increased genomic instability, thereby promoting tumorigenesis. T_h17 cell differentiation can be influenced by tryptophan metabolites and T_h17-mediated inflammation has been implicated in liver cancer. Whether tryptophan metabolism in cancer cells influences tumour progression by modulating immune cells remains to be seen. (B) Metabolic competition for glucose between cancer cells and tumour-infiltrating T cells. In the proximity of highly glycolytic cancer cells, T cells fail to sustain cytoplasmic calcium levels necessary to activate the NFAT transcription factor, which mediates anti-tumour responses of T cells. The immunosuppressive molecule PD-L1 in cancer cells, may further promote glucose metabolism by signalling through the mechanistic target of rapamycin (mTOR) pathway, in addition to suppressing T cells via interaction with PD-1. ER, endoplasmic reticulum; NFAT, nuclear factor of activated T cells; PD-1, programmed cell death protein 1; PD-L1, PD ligand 1; PEP; phosphoenolpyruvate; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; TCR, T-cell receptor; TDO, tryptophan dioxygenase.