Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming

Abstract

Cancer cells are well-known for adapting their metabolism to maintain high proliferation rates and survive in unfavorable environments with low oxygen and nutritional deficiency. Metabolic reprogramming most commonly arises from the tumor microenvironment (TME). The events of metabolic pathways include the Warburg effect, shift in Krebs cycle metabolites, and increase rate of oxidative phosphorylation that provides the energy for the development and invasion of cancer cells. The TME and shift in tumor metabolism shows a close relationship through bidirectional signaling pathways between the stromal and tumor cells. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in the TME and consist of a heterogeneous and plastic population that play key roles in tumor growth and metastatic capacity. Emerging evidence suggests that CAFs act as major regulators in shaping tumor metabolism especially through the dysregulation of several metabolic pathways, including glucose, amino acid, and lipid metabolism. The arrangement of these metabolic switches is believed to shape distinct CAF behavior and change tumor cell behavior by the CAFs. The crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to cancer cell growth, progression, and evasion from cancer therapies. But the mechanism and process of this interaction remain unclear. This review aimed to highlight the metabolic couplings between tumor cells and CAFs. We reviewed the recent literature supporting an important role of CAFs in the regulation of cancer cell metabolism, and the relevant pathways, which may serve as targets for therapeutic interventions.

Keywords: Cancer; Cancer-associated fibroblasts; Metabolic reprogramming; Tumor microenvironment.

Figure 1

Cancer-associated fibroblasts (CAFs) promote tumor growth through self-metabolic reprogramming: The glycolysis of CAFs was increased in tumor microenvironment, and lactate produced by CAFs was absorbed and utilized by the tumor; CAFs synthesize amino acids through the TCA cycle and amino acids are used by tumor for biosynthesis; In CAFs, lipid metabolism was reprogrammed and LPC was secreted into the microenvironment to promote tumor growth. Abbreviations: GLUT: Glucose transporter; TGF-β: Transforming growth factor-β; ITGB4: Integrin beta 4; MCT1: Monocarboxylate transporter 1; MCT4: Monocarboxylate transporter 4; LPA: Lysophosphatidic acid; LPAR: Lysophosphatidic acid receptor; LPC, lysophosphatidylcholines; TCA, tricarboxylic acid;

Figure 2

Cancer-associated fibroblasts (CAFs) regulating the metabolic reprogramming of tumor cells promote tumor growth. Pathways of CAFs regulating tumor metabolism: secreting exosomes containing nutrient; Secreting cytokines; directly secreting of amino acids and lactic acid; increasing ECM stiffness to regulate tumor metabolism; providing mitochondria; increasing oxidative metabolism. Abbreviations: IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IL-6, interleukin-6; IL-8, interleukin-8; CXCL10, CXC chemokine ligand 10; mTOR, mammalian target of rapamycin; TCA, tricarboxylic acid; PGM1, phosphoglucomutase 1; ECM, extracellular matrix; YAP, Yes-related protein; TAZ, transcriptional co-activator PDZ binding motif.