Fueling the fire or dousing the flame? The unclear role of the free-fatty acid receptor-4 (FFA4/GPR120) in colorectal cancer.

Free-fatty acid receptor-4 (FFA4/GPR120) is a lipid-sensing G protein-coupled receptor that is highly expressed in the colon and strongly implicated in metabolic regulation and inflammation. Existing evidence indicates that FFA4 also modulates colorectal cancer (CRC) biology, however, its role remains paradoxical, poorly defined, and context dependent. Studies in human tissues, CRC cell lines, and animal models report both tumor-promoting and tumor-suppressive effects and interpretation of the current literature is complicated by several challenges, including unclear expression and functional role of its related receptor FFA1, the use of dual FFA1/FFA4 agonists in early studies, shared endogenous ligands, two FFA4 isoforms that are expressed within the colon, and the confounding variable of ligand-directed signaling bias, which is often unexplored. Emerging evidence that FFA1 and FFA4 may exert counter-regulatory effects in cancer cells further complicates attribution of observed phenotypes to a single receptor. Here, we provide a comprehensive update on the body of literature on FFA4 in CRC tissues, cell lines, and animal models of CRC and discuss these challenges, which suggest that much work remains to better characterize the role of this receptor in CRC.