Elucidation of high-fat diet-inbduced inflammation and application to treatment for prostate cancer

• Project/Area Number: 18K16693
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Osaka University
• Principal Investigator: Hayashi Takuji 大阪大学, 大学院医学系研究科, 招へい教員 (50747079)
• Project Period (FY): 2021-03-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 前立腺癌 / 免疫細胞 / 炎症反応 / 腸内細菌叢 / 高脂肪食 / 肥満 / モデルマウス / 炎症

Outline of Research at the Start

我々は遺伝子改変前立腺癌モデルマウスに高脂肪食を投与するとIL6シグナルを介した炎症反応によって癌の進展が促進されることを明らかにしたが、高脂肪食によって局所の炎症が起こる詳細な機序は不明である。高脂肪食は腸内細菌叢を変化させることで大腸癌の発症を促進し、抗生剤により抑制されることが報告されている。我々のモデルマウスにおいても高脂肪食による前立腺組織の炎症と腸内細菌叢が関連しているのか評価し、それを抑制する薬剤が前立腺癌の治療および発症予防に有効であるか検討する。

Outline of Final Research Achievements

High-fat diet (HFD) induced local inflammation and accelerated tumor growth via IL6/pSTAT3 pathway in autochthonous genetically-engineered model mice which corresponds to somatic mutations of human prostate cancer. These phenomena were accompanied with the macrophage polarization and the increase of myeloid-derived suppressor cells (MDSCs) in prostate cancer. In human, tumor-infiltrating MDSCs were increased in obese patients with prostate cancer. Both celecoxib, one of non-steroidal anti-inflammatory drugs, and metformin inhibited these inflammatory responses and tumor growth in the model mice.
Intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells. HFD promotes prostate cancer growth through histamine signaling via mast cells. HFD-induced gut dysbiosis might be involved in the inflammatory cancer growth.

Academic Significance and Societal Importance of the Research Achievements

肥満前立腺癌患者における免疫細胞を介した前立腺癌増殖のメカニズムが明らかとなり、局所でのIL6シグナルは前立腺癌治療のターゲットとなり得ることが示唆された。
また腸内細菌叢の変化および肥満細胞でのヒスタミンシグナルが高脂肪食による前立腺癌増殖の促進に関与していることがわかり、食事・免疫細胞・前立腺癌との相互作用の解明を進めることによって、前立腺癌の発症予防や増殖抑制による新規治療法の開発に大きく寄与できると考えられた。

Research Products

• [Int'l Joint Research] Department of Pathology, UAB(米国)
• [Int'l Joint Research] Department of Pathology, UAB(米国)
• [Int'l Joint Research] Department of Pathology, UAB(米国)
• [Journal Article] High-fat diet promotes prostate cancer growth through histamine signaling. (2022)
  • Author(s): Matsushita M, Fujita K, Hatano K, Hayashi T, Kayama H, Motooka D, Hase H, Yamamoto A, Uemura T, Yamamichi G, Tomiyama E, Koh Y, Kato T, Kawashima A, Uemura M, Nojima S, Imamura R, Mubeen A, Netto GJ, Tsujikawa K, Nakamura S, Takeda K, Morii E, Nonomura N.
  • Journal Title: Int J Cancer Volume: in press Issue: 4 Pages: 623-636
  • DOI: 10.1002/ijc.34028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gut Microbiota-Derived Short-Chain Fatty Acids Promote Prostate Cancer Growth via IGF1 Signaling. (2021)
  • Author(s): Matsushita M, Fujita K, Hayashi T, Kayama H, Motooka D, Hase H, Jingushi K, Yamamichi G, Yumiba S, Tomiyama E, Koh Y, Hayashi Y, Nakano K, Wang C, Ishizuya Y, Kato T, Hatano K, Kawashima A, Ujike T, Uemura M, Imamura R, Rodriguez Pena MDC, Gordetsky JB, Netto GJ, Tsujikawa K, Nakamura S, Takeda K, Nonomura N.
  • Journal Title: Cancer Research Volume: 81 Issue: 15 Pages: 4014-4026
  • DOI: 10.1158/0008-5472.can-20-4090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Obesity, Inflammation, and Prostate Cancer. (2019)
  • Author(s): Fujita K, Hayashi T, Matsushita M, Uemura M, Nonomura N.
  • Journal Title: J Clin Med. Volume: 8 Issue: 2 Pages: 201-25
  • DOI: 10.3390/jcm8020201
  • Peer Reviewed / Open Access
• [Journal Article] High-fat diet-induced inflammation accelerates prostate cancer growth via IL6 signaling (2018)
  • Author(s): Takuji Hayashi, Kazutoshi Fujita, Satoshi Nojima, et al.
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 17 Pages: 4309-4318
  • DOI: 10.1158/1078-0432.ccr-18-0106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metformin inhibits prostate cancer growth induced by high-fat diet in Pten-deficient model mice (2018)
  • Author(s): Takuji Hayashi, Kazutoshi Fujita, Makoto Matsushita, Yujiro Hayashi, Motohide Uemura, Norio Nonomura
  • Journal Title: International Journal of Urology Volume: 26 Issue: 2 Pages: 307-309
  • DOI: 10.1111/iju.13847
  • Peer Reviewed / Open Access
• [Presentation] 前立腺癌モデルマウスにおいて、高脂肪食による局所での炎症・免疫反応はIL6シグナルを介して癌の進展を促進する (2018)
  • Author(s): 林 拓自、藤田和利、野島 聡、林裕次郎、神宮司健太郎、加藤大悟、河嶋厚成、氏家 剛、永原 啓、植村元秀、森井英一、辻川和丈、野々村祝夫
  • Organizer: 第106回日本泌尿器科学会総会