Metabolic Reprogramming of Colorectal Cancer Cells and the Microenvironment: Implication for Therapy

Abstract

Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.

Keywords: CRC therapy; colorectal cancer; intestinal microbiota; metabolism; the tumor microenvironment.

Figure 1

Altered glucose and glutamine metabolism in CRC. Dysregulated enzymes are represented with ↑ indicating upregulation. Glucose is uptaken by the cell through GLUT1 transporter and is further metabolized by different enzymatic reactions. Cancer cells are favoring lactate accumulation through upregulating enzymes such as LDH. Detailed information is provided in the text.2PG: 2-phosphoglycerate; PEP: phosphoenolpyruvate; PDH: pyruvate dehydrogenase.

Figure 2

The folate and methionine cycle of one-carbon metabolism, as described in the text in detail.

Figure 3

Altered lipid metabolism in CRC. Dysregulated enzymes contributing to abnormal lipogenesis and FAO are clearly represented, with ↑ indicating upregulation, ↓ downregulation and ↓↑ downregulation at an early stage of carcinogenesis and upregulation later in metastatic cancer. TG: triglyceride.

Figure 4

Depiction of tumor mass localized in the colon. Zoomed-in illustration of the tumor microenvironment (TME), including tumor cells, stromal cells and immune cells. Tumor cells with proximity to the blood vessel are marked as oxygenated while distant cells are referred to as hypoxic. The complex networking contains different types of cells, an extracellular matrix (ECM) and molecules such as cytokines, chemokines and microvesicles (such as exosomes).

Figure 5

The Warburg effect (aerobic glycolysis) and oxidative phosphorylation (OXPHO) in cancer cells. (a) Due to the different localization of cancer cells and consequently different oxygen gradient and supply, glucose can be either converted to lactate or to CO2 through TCA and electron chain transport (TCA cycle, ETC), producing energy in the form of ATP as 2 ATPs and 32–36 ATPs, respectively. (b) Metabolic crosstalk between cancer cells and cancer-associated fibroblast (CAFs). Lactate produced in CAFs is transported to the cancer cells via MCT-4 and MCT-1 transporters. In cancer cells, lactate is converted into pyruvate, which is coupled further to the TCA cycle. In addition, increased expression of FASN in CAFs leads to an enhanced level of fatty acids transported into cancer cells through CD36 and used for lipid synthesis, causing increased lipid droplet (LD) formation. Glutamine produced in CAFs affects TCA cycle in cancer cells, while ammonia from cancer cells influences the function of CAFs.