Colorectal Cancer and Metabolism

Abstract

Purpose of review: Metabolic reprogramming is essential for the rapid proliferation of cancer cells and is thus recognized as a hallmark of cancer. In this review, we will discuss the etiologies and effects of metabolic reprogramming in colorectal cancer.

Recent findings: Changes in cellular metabolism may precede the acquisition of driver mutations ultimately leading to colonocyte transformation. Oncogenic mutations and loss of tumor suppressor genes further reprogram CRC cells to upregulate glycolysis, glutaminolysis, one-carbon metabolism, and fatty acid synthesis. These metabolic changes are not uniform throughout tumors, as subpopulations of tumor cells may rely on different pathways to adapt to nutrient availability in the local tumor microenvironment. Finally, metabolic cross-communication between stromal cells, immune cells, and the gut microbiota enable CRC growth, invasion, and metastasis.

Summary: Altered cellular metabolism occurs in CRC at multiple levels, including in the cells that make up the bulk of CRC tumors, cancer stem cells, the tumor microenvironment, and host-microbiome interactions. This knowledge may inform the development of improved screening and therapeutics for CRC.

Keywords: Cancer stem cells; Colorectal cancer; Metabolism; Microbiome; Tumor microenvironment; Warburg effect.

Fig. 1

Overview of metabolic reprogramming in CRC. Metabolic processes and enzymes (emphasized in this review) that are upregulated in CRC cells with a Warburg phenotype are shown in green, while those that are downregulated in CRC are shown in red. Abbreviations: 1CM, one-carbon metabolism; αKG, α-ketoglutarate; ATP, adenosine triphosphate; CAF, cancer-associated fibroblast; COX2, cyclooxygenase-2; CSC, cancer stem cell; ETC, electron transport chain; F6P, fructose-6-phosphate; FA, fatty acid; FADH2, reduced flavin adenine dinucleotide; FAO, fatty acid oxidation; FASN, fatty acid synthase; G6P, glucose-6-phosphate; GDH, glutamate dehydrogenase; Gln, glutamine; GLS, glutaminase; Glu, glutamate; GLUT, glucose transporter; Gly, glycine; GSH, glutathione; Hcy, homocysteine; HDAC, histone deacetylase; HK, hexokinase; LDH5, lactate dehydrogenase5; MCT4, monocarboxylate transporter4; Met, methionine; meTHF, 5,10-methylene THF; MPC, mitochondrial pyruvate carrier; mTHF, 5-methyl THF; NADH, reduced nicotinamide adenine dinucleotide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PFK, phosphofructokinase; PGE2, prostaglandin E2; PHGDH, phosphoglycerate dehydrogenase; PKM2, pyruvate kinase isozyme M2; PPP, pentose phosphate pathway; SAH, S-adenosyl-L-homocysteine; SAM, S-adenosylmethionine; Ser, serine; TCA cycle, tricarboxylic acid cycle; THF, tetrahydrofolate