High-fat diet promotes prostate cancer growth through histamine signaling
Makoto Matsushita
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorCorresponding Author
Kazutoshi Fujita
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Department of Urology, Kindai University, Faculty of Medicine, Osakasayama, Japan
Correspondence
Kazutoshi Fujita, Department of Urology, Kindai University Faculty of Medicine, 377-2 Oono-higashi, Osakasayama, Osaka 589-8511 Japan.
Email: [email protected]
Search for more papers by this authorKoji Hatano
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorTakuji Hayashi
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorHisako Kayama
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan
WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
Institute for Advanced Co-Creation Studies, Osaka University, Suita, Japan
Search for more papers by this authorDaisuke Motooka
Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
Search for more papers by this authorHiroaki Hase
Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan
Search for more papers by this authorAkinaru Yamamoto
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorToshihiko Uemura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorGaku Yamamichi
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorEisuke Tomiyama
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorYoko Koh
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorTaigo Kato
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorAtsunari Kawashima
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorMotohide Uemura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorSatoshi Nojima
Department of Pathology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorRyoichi Imamura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorAysha Mubeen
Department of Pathology, UAB School of Medicine, Birmingham, Alabama, USA
Search for more papers by this authorGeorge J. Netto
Department of Pathology, UAB School of Medicine, Birmingham, Alabama, USA
Search for more papers by this authorKazutake Tsujikawa
Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan
Search for more papers by this authorShota Nakamura
Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
Search for more papers by this authorKiyoshi Takeda
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan
WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
Search for more papers by this authorEiichi Morii
Department of Pathology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorNorio Nonomura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorMakoto Matsushita
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorCorresponding Author
Kazutoshi Fujita
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Department of Urology, Kindai University, Faculty of Medicine, Osakasayama, Japan
Correspondence
Kazutoshi Fujita, Department of Urology, Kindai University Faculty of Medicine, 377-2 Oono-higashi, Osakasayama, Osaka 589-8511 Japan.
Email: [email protected]
Search for more papers by this authorKoji Hatano
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorTakuji Hayashi
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorHisako Kayama
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan
WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
Institute for Advanced Co-Creation Studies, Osaka University, Suita, Japan
Search for more papers by this authorDaisuke Motooka
Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
Search for more papers by this authorHiroaki Hase
Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan
Search for more papers by this authorAkinaru Yamamoto
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorToshihiko Uemura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorGaku Yamamichi
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorEisuke Tomiyama
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorYoko Koh
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorTaigo Kato
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorAtsunari Kawashima
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorMotohide Uemura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorSatoshi Nojima
Department of Pathology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorRyoichi Imamura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorAysha Mubeen
Department of Pathology, UAB School of Medicine, Birmingham, Alabama, USA
Search for more papers by this authorGeorge J. Netto
Department of Pathology, UAB School of Medicine, Birmingham, Alabama, USA
Search for more papers by this authorKazutake Tsujikawa
Laboratory of Cell Biology and Physiology, Osaka University, Graduate School of Pharmaceutical Sciences, Suita, Japan
Search for more papers by this authorShota Nakamura
Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
Search for more papers by this authorKiyoshi Takeda
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan
WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
Search for more papers by this authorEiichi Morii
Department of Pathology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorNorio Nonomura
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan
Search for more papers by this authorFunding information: Japan Society for the Promotion of Science, Grant/Award Number: JP21K09421; Japanese Urological Association; Yakult Bio-Science Foundation
Abstract
Western high-fat diets (HFD) are regarded as a major risk factor for prostate cancer (PCa). Using prostate-specific Pten-knockout mice as a PCa model, we previously reported that HFD promoted inflammatory PCa growth. The composition of the gut microbiota changes under the influence of diet exert various effects on the host through immunological mechanisms. Herein, we investigated the etiology of HFD-induced inflammatory cancer growth and the involvement of the gut microbiome. The expression of Hdc, the gene responsible for histamine biosynthesis, and histamine levels were upregulated in large prostate tumors of HFD-fed mice, and the number of mast cells increased around the tumor foci. Administration of fexofenadine, a histamine H1 receptor antagonist, suppressed tumor growth in HFD-fed mice by reducing the number of myeloid-derived suppressor cells and suppressing IL6/STAT3 signaling. HFD intake induced gut dysbiosis, resulting in the elevation of serum lipopolysaccharide (LPS) levels. Intraperitoneal injection of LPS increased Hdc expression in PCa. Inhibition of LPS/Toll-like receptor 4 signaling suppressed HFD-induced tumor growth. The number of mast cells increased around the cancer foci in total prostatectomy specimens of severely obese patients. In conclusion, HFD promotes PCa growth through histamine signaling via mast cells. Dietary high-fat induced gut dysbiosis might be involved in the inflammatory cancer growth.
Graphical Abstract
What's new?
High-fat diets consisting of large amounts of animal fat are linked to an increased risk of prostate cancer, an association attributed in part to the ability of excess fat to induce inflammation in prostate immune cells. While the mechanism behind this phenomenon is unknown, the present study shows that high animal fat intake promotes prostate cancer growth via histamine signaling by mast cells. In addition, in mice, gut dysbiosis induced by a high-fat diet resulted in elevated lipopolysaccharide (LPS) levels, whereas inhibition of LPS signaling suppressed tumor growth. The findings reveal novel links between fat intake and inflammation in cancer.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The reported cDNA microarray data are available at GEO under the accession number GSE184381. Other data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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