Androgens such as testosterone and dihydrotestosterone are essential for male reproduction and sexual function. Androgens can also influence the growth of prostate tumor cells, and androgen deprivation therapy (ADT) either by surgical means (castration) or pharmacological approaches (hormone suppression), is the cornerstone of current prostate cancer treatments. Pernigoni et al. found that when the body was deprived of androgens during ADT, the gut microbiome could produce androgens from androgen precursors (see the Perspective by McCulloch and Trinchieri). Gut commensal microbiota in ADT-treated patients or castrated mice produced androgens that were absorbed into the systemic circulation. These microbe-derived androgens appeared to favor the growth of prostate cancer and helped to facilitate development into a castration- or endocrine therapy–resistant state. —PNK
The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and Prevotella stercorea administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.
雄激素如睾酮和二氢睾酮对男性生殖和性功能至关重要。雄激素也能影响前列腺肿瘤细胞的生长，而雄激素剥夺疗法（ADT）无论是通过外科手段（去势）还是药理学方法（激素抑制），都是当前前列腺癌治疗的基石。Pernigoni等人发现，在ADT期间身体被剥夺雄激素时，肠道微生物组可以从雄激素前体产生雄激素（参见McCulloch和Trinchieri的视角）。在ADT治疗的患者或去势小鼠中，肠道共生微生物产生了被吸收到体循环中的雄激素。这些微生物来源的雄激素似乎有利于前列腺癌的生长，并有助于促进发展为去势或内分泌疗法抵抗状态。—PNK
微生物群包括与宿主密切接触的微生物，双方互惠互利。肠道微生物群对去势抵抗性前列腺癌（CRPC）出现的贡献尚未得到解决。我们发现，在小鼠和人类中，雄激素剥夺促进了特定共生微生物群的扩张，这有助于小鼠去势抵抗的发生。具体来说，CRPC小鼠和患者的肠道微生物群落富含能够将雄激素前体转化为活性雄激素的物种。通过抗生素治疗消除肠道微生物群延迟了去势抵抗的出现，即使在免疫缺陷小鼠中也是如此。来自CRPC小鼠和患者的粪便微生物群移植（FMT）使携带前列腺癌的小鼠对去势产生抵抗。相反，来自激素敏感性前列腺癌患者的FMT和Prevotella stercorea的给药控制了肿瘤生长。这些结果表明，共生肠道微生物群通过提供雄激素的替代来源，促进了CRPC的内分泌抵抗。
Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis
肿瘤(癌症)患者之家