Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy

Abstract

The tumor microenvironment (TME) is an ensemble of non-tumor cells comprising fibroblasts, cells of the immune system, and endothelial cells, besides various soluble secretory factors from all cellular components (including tumor cells). The TME forms a pro-tumorigenic cocoon around the tumor cells where reprogramming of the metabolism occurs in tumor and non-tumor cells that underlies the nature of interactions as well as competitions ensuring steady supply of nutrients and anapleoretic molecules for the tumor cells that fuels its growth even under hypoxic conditions. This metabolic reprogramming also plays a significant role in suppressing the immune attack on the tumor cells and in resistance to therapies. Thus, the metabolic cooperation and competition among the different TME components besides the inherent alterations in the tumor cells arising out of genetic as well as epigenetic changes supports growth, metastasis, and therapeutic resistance. This review focuses on the metabolic remodeling achieved through an active cooperation and competition among the three principal components of the TME-the tumor cells, the T cells, and the cancer-associated fibroblasts while discussing about the current strategies that target metabolism of TME components. Further, we will also consider the probable therapeutic opportunities targeting the various metabolic pathways as well as the signaling molecules/transcription factors regulating them for the development of novel treatment strategies for cancer.

Keywords: Warburg effect; cancer cell metabolism; cancer-associated fibroblasts; immune network; metabolic cooperation; metabolic reprogramming; tumor microenvironment.

Figure 1

Metabolic programing, reprograming, competition, and cooperation between cells of the TME. The modulation of signaling pathways and metabolic enzymes as well as availability, levels, and exchange of several metabolites decide the fate of the tumor growth by affecting the functions and differentiation of various subsets of immune cells, generation of CAFs and CAAs, and proliferation of endothelial cells. FAO, fatty acid oxidation; FFA, free fatty acids; DC, dendritic cells; MØ: macrophages; TME, tumor microenvironment; CAFs, cancer-associated fibroblasts; CAAs, cancer-associated adipocytes.

Figure 2

Metabolic reprogramming between cancer-associated fibroblasts (CAFs) and tumor cells within tumor microenvironment.