Metabolism and Colorectal Cancer

Abstract

Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment.

Keywords: colorectal cancer; diet; metabolism; microbiome.

Figure 1

Schematic of the colonic crypt and associated epithelial and mesenchymal cell types. Figure adapted from images created with BioRender.com. Abbreviations: ISC, intestinal stem cell; Lgr5⁺, leucine-rich repeat–containing G protein–coupled receptor 5 positive.

Figure 2

Effect of pro-obesity diets on intestinal epithelium and CRC tumorigenesis. (a) A high-fructose diet increases villi length, fatty acid synthesis, and aerobic glycolysis and reduces M2 pyruvate kinase expression, promoting CRC tumorigenesis and liver metastasis. Arriving CRC cells adapt to the liver by using readily available fructose as a carbon source by upregulating aldolase B. (b) A high-fat diet induces increases in ISC self-renewal, stemness, FAO via PPAR, and genotoxic bile acids, a decrease in MHC-II expression on intestinal epithelial cells, dysbiosis, and a reduction in CD8⁺ T cells, thereby promoting CRC tumorigenesis. Figure adapted from images created with BioRender.com. Abbreviations: CRC, colorectal cancer; FAO, fatty-acid oxidation; ISC, intestinal stem cell; MHC-II, major histocompatibility complex class II; PPAR, peroxisome proliferator-activated receptor.

Figure 3

An HFD promotes CRC tumorigenesis through intestinal dysbiosis and decreased tumor immune surveillance. Beyaz et al. (32) found that an HFD reduces microbial diversity, particularly Helicobacter sp. and Odoribacter sp., leading to a decrease in MHC-II expression on intestinal epithelial cells and a reduction in antitumor immunity. Yang et al. (98) reported that an HFD promotes tumorigenesis through a shift in protective Parabacteroides distasonis to Alistipes sp. and an increase in the concentration of the protumorigenic fatty acid, lysophosphatidic acid. Figure adapted from images created with BioRender.com. Abbreviations: CRC, colorectal cancer; HFD, high-fat diet; IFN, interferon; MHC-II, major histocompatibility complex class II.

Figure 4

Metabolic pathways exploited in CRC initiation and progression. At homeostasis, ISCs sustain high proliferation through upregulated glycolysis, FAO, cholesterol metabolism, shuttling lactate toward biosynthetic pathways through downregulation of MPC, and lactate secretion from adjacent Paneth cells. Adenomas exploit these pathways and sustain high proliferation through perturbations in oncogenes and tumor suppressors, enhancing glycolysis, nucleotide synthesis, and FAO. CRC further manipulates these same pathways and others, including the serine synthesis pathway, angiogenesis, and lipogenesis. Additional metabolic adaptations are required for metastasis, including increased FAO to resist anoikis, glutathione production, PGE₂, and lysine degradation. CRC cells arriving at the liver adapt to the harsh microenvironment through upregulating CKB for extracellular sources of energy, aldolase B for fructose metabolism, and gluconeogenesis. Figure adapted from images created with BioRender.com. Abbreviations: CKB, creatine kinase, brain-type; CRC, colorectal cancer; FAO, fatty-acid oxidation; ISC, intestinal stem cell; MPC, mitochondrial pyruvate carrier; PGE₂, prostaglandin E₂.