Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications

Abstract

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.

Keywords: Colorectal cancer; Metastasis; Therapeutics; Tumor microenvironment; Warburg effect.

Fig. 1

A Aerobic glycolysis in cancer. The transportation of extracellular glucose to the cytoplasm is achieved by glucose transporters (GLUTs). Hexokinase (HK) catalyzes the conversion of glucose to glucose-6-phosphate (G6P) and the conversion of Glucose-6-phosphate to fructose-6-phosphate (F6P) is a reversible reaction. The F6P can be catalyzed into fructose-1,6-biphosphate (F1,6BP) by phosphofructokinase1 (PFK-1). F1,6BP is converted into phosphoenolpyruvate (PEP) through a series of reversible reactions. Pyruvate kinase (PK) was responsible for catalyzing PEP into pyruvate and pyruvate can reversibly transformed to lactate by lactate dehydrogenase (LDH). Finally, lactate is transported out of cells which relies on the monocarboxylate transporter/MCT family. Carbonic anhydrases IX (CAIX) can export redundant protons and lactate and maintain the acid–base balance. In addition, the intermediates in glycolysis can enter other metabolic processes including hexosamine pathway, pentose phosphate pathway, lipid metabolism, TCA cycle, amino acid metabolism and one-carbon metabolism to synthesize biomacromolecules and meet the urgent growth needs of tumors. Arrows indicate positive modulations or transitions, while blunt ends indicate negative modulations. B The genetic phenotype in CRC regulates glycolysis. Mutations in APC lead to β-catenin/TCF transcriptional activation which induces increased transcription of β-catenin target genes to increase glycolysis. Inactivating mutations or deletion in the TP53 gene inhibits HIF1A, MYC, GLUTs, HK2, F2,6BP and MCT1 to reduce glycolysis. p53-induced upregulation of parkin can accelerate the degradation of HIF1. Activating mutations in RAS and the overexpression of EGFR trigger the activation of downstream pathways including PI3K/AKT/mTORC1 axis to promote glycolysis by enhancing glucose uptake, phosphorylating glycolytic enzymes and transcriptionally regulating glucose transporters and glycolytic enzymes expression via transcription factors such as HIF1A and MYC. Arrows indicate positive modulations or transitions, while blunt ends indicate negative modulations

Fig. 2

How glycolytic metabolism supports CRLM. Colorectal cancer liver metastasis (CRLM) relies on a small proportion of CRC cells which acquire a series of features including epithelial-to-mesenchymal transition (EMT), cell migration through extracellular matrix (ECM), stemness and redox homeostasis. Aerobic glycolysis could support these processes to accelerate metastasis. Arrows indicate positive modulations or transitions, while blunt ends indicate negative modulations

Fig. 3

Glycolytic metabolism remodels tumor microenvironment. Lactate can promote tumor cells and tumor-associated macrophages (TAMs) to secret a series of factors to support angiogenesis. Endothelial cells can also sense the extracellular lactate level to promote their proliferation. Glucose deprivation and extracellular acidosis significantly suppresses the anti-tumor function of macrophages, CD4⁺ T cells, CD8⁺ T cells and dendritic cells (DCs) while has little influence on immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Carcinoma-associated fibroblasts (CAFs) and cancer cells can promote the glycolytic levels of each other. Additionally, a part of tumor cells can uptake lactate and display oxidative metabolism, also known as “the reverse Warburg effect.” Arrows indicate positive modulations or transitions, while blunt ends indicate negative modulations

Fig. 4

Summary of glycolysis-based therapeutic strategies for CRC. Arrows indicate positive modulations or transitions, while blunt ends indicate negative modulations