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

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Gut Microbiota Promotes Obesity-Associated Liver Cancer Through PGE 2-Mediated Suppression of Antitumor Immunity Published OnlineFirst February 15, 2017; DOI: 10.1158/2159-8290.CD-16-0932 RESEARCH ARTICLE Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity Tze Mun Loo1, Fumitaka Kamachi1, Yoshihiro Watanabe1, Shin Yoshimoto2,3, Hiroaki Kanda4, Yuriko Arai1,2, Yaeko Nakajima-Takagi5, Atsushi Iwama5, Tomoaki Koga6, Yukihiko Sugimoto6, Takayuki Ozawa1, Masaru Nakamura1, Miho Kumagai1, Koichi Watashi7,8, Makoto M. Taketo9, Tomohiro Aoki10, Shuh Narumiya10,11,12, Masanobu Oshima12,13, Makoto Arita14,15,16,17, Eiji Hara2,12,18, and Naoko Ohtani1,16 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 transloca- tion 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 progres- sion. 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); 1–17. ©2017 AACR. 1Department of Applied Biological Science, Faculty of Science and Tech- Medical Sciences, Kanagawa, Japan. 15Graduate School of Medical Life nology, Tokyo University of Science, Chiba, Japan. 2Division of Cancer Biol- Science, Yokohama City University, Kanagawa, Japan. 16PRESTO, Japan ogy, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Science and Technology Agency, Kawaguchi, Saitama, Japan. 17Division of Japan. 3LSI Medience Corporation, Tokyo, Japan. 4Division of Pathology, Physiological Chemistry and Metabolism, Graduate School of Pharmaceu- Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. tical Sciences, Keio University, Tokyo, Japan. 18Department of Molecular 5Department of Cellular and Molecular Medicine, Graduate School of Microbiology, Research Institute for Microbial Diseases, Osaka Univer- Medicine, Chiba University, Chiba, Japan. 6Department of Pharmaceutical sity, Osaka, Japan. Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto Note: Supplementary data for this article are available at Cancer Discovery 7 University, Kumamoto, Japan. Department of Virology II, National Insti- Online (http://cancerdiscovery.aacrjournals.org/). tute of Infectious Diseases, Tokyo, Japan. 8CREST, Japan Science and Technology Agency (JST), Saitama, Japan. 9Department of Pharmacol- Current address for N. Ohtani: Department of Pathophysiology, Osaka City ogy, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, University, Graduate School of Medicine, Osaka, Japan. Kyoto, Japan. 10Center for Innovation in Immunoregulation Technology Corresponding Author: Naoko Ohtani, Department of Pathophysiology, and Therapeutics, Kyoto University Graduate School of Medicine, Konoe- Osaka City University, Graduate School of Medicine, Asahimachi 1-4-3, cho Yoshida, Kyoto, Japan. 11Medical Innovation Center, Kyoto University Abeno-ku, Osaka, 545-8585, Japan. Phone: 81-6-6645-3710; Fax: 81-6- Graduate School of Medicine, Kyoto, Japan. 12AMED-CREST, AMED, Japan 6645-3712; E-mail: [email protected] 13 Agency for Medical Research and Development, Tokyo, Japan. Division doi: 10.1158/2159-8290.CD-16-0932 of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 14Laboratory for Metabolomics, RIKEN Center for Integrative ©2017 American Association for Cancer Research. OF1 | CANCER DISCOVERY MAY 2017 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst February 15, 2017; DOI: 10.1158/2159-8290.CD-16-0932 INTRODUCTION metabolite deoxycholic acid (DCA) facilitates HCC develop- ment by inducing cellular senescence and the senescence- Obesity has become a worldwide health problem and is associated secretory phenotype (SASP) in hepatic stellate cells known to increase the risk of diabetes, cardiovascular disease, (HSC) in the tumor microenvironment. This recently identi- and several types of cancer (1). Although hypernutrition- fied phenotype of senescent cells involves secretion of a series related systemic alterations are thought to be involved in of inflammatory cytokines, chemokines, matrix-remodeling cancer development (2–4), the molecular mechanisms that factors, and growth factors (7), suggesting that the gut–liver integrate these events still remain largely unclear. Among axis plays a pivotal role in inducing cellular senescence of obesity-associated cancers, liver cancer has been shown to HSCs and liver tumorigenesis (4). The importance of the have a strong relationship with obesity, based on epidemio- SASP phenotype has also been recognized in vivo in a variety logical studies (1). The most common risk factor for hepato- of pathophysiologic contexts, giving rise to not only deleteri- cellular carcinoma (HCC) is long-term infection by hepatitis ous effects such as chronic inflammation and tumorigenesis B virus (HBV) or hepatitis C virus (HCV; ref. 5). However, (4, 8, 9), but also beneficial effects such as embryonal develop- obesity-associated nonalcoholic fatty liver disease (NAFLD) ment (10, 11), immunosurveillance (12–14), and tissue repair and nonalcoholic steatohepatitis (NASH) have recently (15, 16), depending on the biological context. Indeed, the emerged as important risk factors for liver cancer (6). There- paracrine effects of SASP have been reported to be dependent fore, elucidation of the precise molecular mechanisms medi- on the surrounding cells (17), particularly on the p53 status ating the development of obesity-induced NASH-associated of these cells (18). Accumulating evidence has indicated that HCC is urgently needed. SASP is regulated by a combination of several transcription We previously reported that increased enterohepatic cir- factors, epigenetic regulators, and metabolic pathways, in culation of the obesity-induced Gram-positive gut microbial response to DNA damage (19–23). DCA can create DNA MAY 2017 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst February 15, 2017; DOI: 10.1158/2159-8290.CD-16-0932 RESEARCH ARTICLE Loo et al. damage by elevating the levels of reactive oxygen species (Fig. 1B–D). Senescence markers, such as upregulation of p21 (ROS), thereby inducing cellular senescence and the SASP and the DNA damage response marker 53BP1, were detected to promote obesity-associated HCC (4). However, the trigger in HSCs in the livers of mice fed DCA and an ND, reaching that initiates the SASP signals may vary depending on physi- levels similar to those in the livers of HFD-fed mice at 30 weeks ologic status, and thus the precise mechanisms regulating (Fig. 1E). However, at this time point, the frequency of SASP the expression of SASP factors need to be elucidated in each induction in HSCs was much lower in livers from mice fed DCA pathophysiologic setting (24). and an ND as compared with that in mice fed an HFD (Fig. 1E, One of the mechanisms that may trigger the SASP could be IL1β, Groα, and IL6). We found that mice fed DCA and an ND Toll-like receptor (TLR) signaling. High mobility group box required approximately six more months for complete SASP 1 (HMGB1) activates TLR4-mediated cytokine signals in an induction and HCC development at the 55-week time point autocrine manner in senescent cells (25). In addition, previous (Fig. 1B–E). Therefore, we speculated that other factors underly- in vivo studies have demonstrated that TLR4-mediated inflam- ing the HFD-fed obese liver could be necessary to accelerate the matory signals induced by the Gram-negative bacterial com- effects of DCA in aggressively promoting HCC development. ponent lipopolysaccharide (LPS) are important for promoting Accordingly, we searched for factors that promote obesity- liver fibrosis and fibrosis-associated liver tumorigenesis (26). associated HCC progression, based on (i) the obesity-induced However, in our obesity-associated HCC model, Gram-posi- gut microbial component(s) and (ii) the increased lipid storage tive bacteria, but not Gram-negative bacteria, were found to in the liver tumor areas of HFD-fed obese mice. be dramatically increased in obese mice fed a high-fat diet (HFD; ref. 4), consistent with previous reports (27). Moreover, LTA- and TLR2-Mediated Signaling Promotes
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