Matsushita Makoto, Fujita Kazutoshi, Hayashi Takuji, Kayama Hisako, Motooka Daisuke, Hase Hiroaki, Jingushi Kentaro, Yamamichi Gaku, Yumiba Satoru, Tomiyama Eisuke, Koh Yoko, Hayashi Yujiro, Nakano Kosuke, Wang Cong, Ishizuya Yu, Kato Taigo, Hatano Koji, Kawashima Atsunari, Ujike Takeshi, Uemura Motohide, Imamura Ryoichi, Rodriguez Pena Maria D C, Gordetsky Jennifer B, Netto George J, Tsujikawa Kazutake, Nakamura Shota, Takeda Kiyoshi, Nonomura Norio
Department of Urology, Osaka University, Graduate School of Medicine, Suita, Japan.
Department of Urology, Kindai University, Faculty of Medicine, Osakasayama, Japan.
Cancer Res. 2021 Aug 1;81(15):4014-4026. doi: 10.1158/0008-5472.CAN-20-4090. Epub 2021 May 26.
Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including and , inhibited prostate cancer cell proliferation, and reduced prostate expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 . Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that 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.
过量摄入动物脂肪及由此导致的肥胖是前列腺癌的主要危险因素。由于已知肠道微生物群的组成会随饮食组成和体型而变化，我们使用前列腺特异性基因敲除小鼠作为前列腺癌模型，来研究动物脂肪摄入与前列腺癌之间是否存在肠道微生物群介导的联系。在喂食含有大量猪油的高脂饮食的荷前列腺癌小鼠中口服抗生素混合物（Abx），会显著改变肠道微生物群的组成，包括[具体微生物名称1]和[具体微生物名称2]，抑制前列腺癌细胞增殖，并降低前列腺[相关指标名称]的表达以及循环胰岛素样生长因子-1（IGF1）水平。在前列腺癌组织中，IGF1受体下游的MAPK和PI3K活性通过给予Abx而受到抑制。IGF1直接促进前列腺癌细胞系DU145和22Rv1的增殖。给予Abx还降低了肠道细菌产生的粪便短链脂肪酸（SCFA）水平。补充SCFAs通过提高IGF1水平促进肿瘤生长。在人类中，发现IGF1在肥胖患者的前列腺癌组织中高表达。总之，肠道微生物产生的SCFAs刺激的IGF1生成通过激活局部前列腺MAPK和PI3K信号通路影响前列腺癌的生长，表明存在肠道微生物群-IGF1-前列腺轴。通过调节肠道微生物群破坏该轴可能有助于前列腺癌的预防和治疗。意义：这些结果表明，肠道细菌通过短链脂肪酸调节宿主全身和局部前列腺的IGF1，这可促进前列腺癌细胞的增殖。
