Fig. 4.

TGF-β-dependent CAF–cancer cell metabolic coupling. 1. TGF-β signaling increases RWE of CAFs via decreasing CAV-1 and IDH3α, while increasing PDK1, PKM2, and ROS. ROS conversely promotes TGF-β signaling, which sustains CAF phenotype. In this way, aerobic glycolysis of CAFs increases and a large amount of lactate molecules are produced. Lactate shuttles from CAFs to cancer cells via MCT-4 and MCT-1. Lactates are then converted to pyruvate and utilized for TCA cycle of cancer cell. 2. Glutamine, ketone body, and BCKAs are also substrates of RWE that are produced by CAFs and then are transferred into cancer cells for TCA cycle of cancer cell. 3. TGF-β-mediated metabolic coupling can also correlate with glycogen metabolism. Cancer cell-derived TGF-β cytokines trigger the TGF-β non-canonical p38-MAPK signaling in CAFs via paracrine, which stimulates the production of several cytokines including IL-6, CXCL10, and CCL5 from CAFs. These cytokines induce glycogen metabolism upregulation in cancer cells via phosphorylation and activation of PGM1, an enzyme that is involved in glycogen synthesis. Then glycogen is accumulated in cancer cells and promotes cancer cell metastasis. Green highlighted items mean TGF-β signaling positively regulates them or they are positively regulated by TGF-β signaling. Red vice versa. And these green and red ones are potentially TGF-β-dependent metabolic targets in cancer. PDK1: pyruvate dehydrogenase kinase 1; ROS: reactive oxygen species; RWE: reverse Warburg effect; BCAAs: branched-chain amino acids; BCKAs: branched-chain α-ketoacids. BCAT1: BCAA transaminases; and PGM1: phosphoglucomutase 1