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.
Highlights
It was found that fatty acids, diglycerides (DGs), phosphatidic acid (PA), phosphatidylinositol (PI), lysophosphatidylcholine (LPC) and phosphatidylethanolamines (PE) were significantly upregulated in cancer-associated fibroblasts (CAFs) compared with normal fibroblasts, accompanied by higher excreted levels of fatty acids and phospholipids [208]
Xing et al observed that rapamycin-resistant CRC cells DLD-1 displayed an elevated glycolytic rate with the upregulation of glycolytic enzymes, including hexokinase 2, PKM2 and Lactate dehydrogenase (LDHA), and a combination of the mTOR inhibitor Rapamycin and the glycolysis inhibitor 3,4,5,7-tetrahydroxyflavone resulted in synergistically suppressive effects [250]
Based on these two hallmarks of cancer, immunotherapy with the checkpoint inhibitor has been successfully applied in the treatment of solid tumors, including CRC; on the other hand, many lines of evidence suggest that metabolic pathways, intersecting with oncogenic pathways, the tumor microenvironment and the intestinal microbiota, may be a targetable vulnerability in CRC
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Colorectal tumorigenesis goes through a series of genetic and epigenetic alterations, including somatic mutations, chromosomal instability, microsatellite instability and DNA methylation, as well as histone acetylation, leading to the activation of oncogenes and the inactivation of tumor suppressor genes [8,9]. Mutation of the tumor suppressor gene APC is detectable in 70% of benign colorectal adenomas, resulting in the inactivation of APC in the majority of colorectal adenomas. Followed by activation of oncogene KRAS due to mutation and the inactivation of the tumor suppressor gene p53, PTEN and SMAD4, most of the colorectal adenomas develop to CRC [8]. While driver mutations in oncogenes and tumor suppressor genes govern metabolic programs, they influence gene expression and epigenetic regulation, and reshape the tumor microenvironment (TME) and the gut microbiota [14]. A better understanding of the metabolic network in CRC will lead to the development of a novel therapeutic strategy in the management of this fatal disease
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