Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE 2-Mediated Suppression of Antitumor Immunity

Cancer Discov. 2017 May;7(5):522-538. doi: 10.1158/2159-8290.CD-16-0932. Epub 2017 Feb 15.

Abstract

Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.Significance: We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. Cancer Discov; 7(5); 522-38. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / microbiology
  • Dinoprostone / metabolism*
  • Female
  • Gastrointestinal Microbiome / physiology*
  • Humans
  • Lipopolysaccharides / metabolism
  • Liver Neoplasms / immunology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / microbiology
  • Male
  • Mice, Inbred C57BL
  • Obesity / complications*
  • Obesity / microbiology
  • Teichoic Acids / metabolism
  • Tumor Escape / immunology
  • Tumor Microenvironment / immunology

Substances

  • Lipopolysaccharides
  • Teichoic Acids
  • lipoteichoic acid
  • Dinoprostone