Metabolic Syndrome Develops Cardia Cancer via Nuclear Factor-E2-related Factor 2-Programmed Death-Ligand 1 Signaling

Area of Science:

• Gastroenterology and Oncology
• Immunology and Metabolism

Background:

• Rising incidence of gastric cardia adenocarcinoma (GCA) parallels metabolic syndrome (MetS).
• Lipopolysaccharide (LPS) is implicated in GCA development and immune checkpoint inhibitor resistance.

Purpose of the Study:

• To investigate if high-fat diet (HFD)-induced endotoxemia promotes GCA progression.
• To determine the role of programmed death-ligand 1 (PD-L1) signaling in this process.

Main Methods:

• K19-Wnt1/C2mE mice were fed HFD or control diets, with or without LPS and clodronate liposomes (CLs).
• Nrf2-deficient K19-Wnt1/C2mE mice were used to assess Nrf2's role in tumorigenesis.
• Experiments involved MKN7 and THP-1 cell lines to elucidate molecular mechanisms.

Main Results:

• HFD + LPS induced GCA progression, characterized by increased tumor proliferation, macrophage infiltration, gut dysbiosis, barrier damage, endotoxemia, and insulin resistance.
• Upregulation of 8-OHdG, Nqo1, TNF-α, p-NFκB, and PD-L1 was observed in tumors; TNF-α was present in tumor cells and macrophages.
• Nrf2 deficiency reduced tumor growth and PD-L1 expression but did not resolve gut barrier damage or endotoxemia; LPS stimulated TNF-α production and NFκB-PD-L1 signaling in cell lines.

Conclusions:

• HFD-related metabolic endotoxemia promotes GCA progression.
• This promotion occurs via PD-L1 induction in tumor cells, mediated by Nrf2 signaling activated by LPS.
• Additionally, LPS-activated macrophages release TNF-α, activating NFκB signaling within the tumor microenvironment.