Lactate-related metabolic reprogramming and immune regulation in colorectal cancer

Abstract

Changes in cellular metabolism involving fuel sources are well-known mechanisms of cancer cell differentiation in the context of carcinogenesis. Metabolic reprogramming is regulated by oncogenic signaling and transcriptional networks and has been identified as an essential component of malignant transformation. Hypoxic and acidified tumor microenvironment contributes mainly to the production of glycolytic products known as lactate. Mounting evidence suggests that lactate in the tumor microenvironment of colorectal cancer(CRC) contributes to cancer therapeutic resistance and metastasis. The contents related to the regulatory effects of lactate on metabolism, immune response, and intercellular communication in the tumor microenvironment of CRC are also constantly updated. Here we summarize the latest studies about the pleiotropic effects of lactate in CRC and the clinical value of targeting lactate metabolism as treatment. Different effects of lactate on various immune cell types, microenvironment characteristics, and pathophysiological processes have also emerged. Potential specific therapeutic targeting of CRC lactate metabolism is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcomes by reducing chemoresistance.

Whole‐transcriptome defines novel glucose metabolic subtypes in colorectal cancer

“…The malignant transformation of tumour cells promotes the evolution of metabolic pathways, 31 while abnormal metabolic molecules, such as lactate and adipokines, act as oncogenic pathway regulators. [32][33][34] CRC is a typical metabolism-related cancer, and diabetes is the most common metabolic disease asso- SFRP2 is a member of the Secreted Frizzled Related Protein family, whose well established function is to inhibit Wnt/β-catenin signalling pathway by binding to Frizzled receptors, inhibiting cell proliferation, migration, and invasion. 35 However, a growing number of studies have shown that SFRP2 is associated with metastasis, poor prognosis and treatment resistance in a variety of malignant diseases, including melanoma, prostate cancer and glioma.…”

“…Abnormal metabolism is a hallmark of cancer, with special energy requirements and excessive proliferation of tumour cells being mutually reinforcing. The malignant transformation of tumour cells promotes the evolution of metabolic pathways, 31 while abnormal metabolic molecules, such as lactate and adipokines, act as oncogenic pathway regulators 32–34 . CRC is a typical metabolism‐related cancer, and diabetes is the most common metabolic disease associated with an increased risk (~40%) for CRC.…”

“…The malignant transformation of tumour cells promotes the evolution of metabolic pathways, 31 while abnormal metabolic molecules, such as lactate and adipokines, act as oncogenic pathway regulators. 32 , 33 , 34 CRC is a typical metabolism‐related cancer, and diabetes is the most common metabolic disease associated with an increased risk (~40%) for CRC. The molecular mechanism underlying this association may involve hyperinsulinemia and insulin resistance.…”