Prominent fibroblast growth factor 21 with less abundant tumor-associated macrophages in hepatic mass of the conditional mgmt-deleted mice using LysM-Cre system.

Abstract

Background: Fibroblast growth factor 21 is a molecule responsible for cell energy regulation, mainly produced from hepatocytes, while O6-methylguanine-DNA methyltransferase is a mandatory enzyme for DNA repair.

Methods: Because tumors in the livers might enhance hepatocytic FGF-21 production for supporting tumor-associated macrophages (TAM) to promote cancers, the intrahepatic tumor injection model was performed.

Results: Indeed, intrahepatic injection of MC38 cells in wild-type mice increased FGF-21 in serum and liver tissue. Murine hepatocytes excreted FGF-21 after induction by cell stresses, lipopolysaccharide, and MC38 supernatant, while human hepatocytes (HepG2) produced FGF-21 after incubation with the conditioned media of CaCO₂, but neither HK2 nor H292. Intrahepatic MC38 injection in mgmt null mice demonstrated a lower tumor size and intratumoral TAM (CD206-positive cells) but higher FGF-21 production when compared with intrahepatic tumors in mgmt control. Additionally, MC38 supernatant induced M2-like polarization, which was enhanced by recombinant FGF-21. Furthermore, TAM induction by MC38 supernatant caused cell stresses only in mgmt null macrophages but not in mgmt control cells, as indicated by increased cell-free DNA and malondialdehyde with reduced maximal respiration. The TAM transformation-induced cell injury was neutralized by recombinant FGF-21.

Conclusion: TAM transformation in mgmt null macrophages induced more severe cell injuries than mgmt control macrophages, leading to the less abundant intratumoral TAM and increased FGF-21 to attenuate the injuries in mgmt null mice with tumors. Further studies on FGF-21 and MGMT in cancers are interesting.