《自然》：肠道细菌会导致前列腺癌的生长和治疗抗性的出现

资讯来源：Institute of Cancer Research

编辑翻译：奇奇

本文献于2021年10月7日发表在国际著名期刊《自然》上。文中科学家们揭示了肠道细菌与前列腺癌和激素疗法的关系，这为开发微生物群治疗策略铺平了道路。

一项新研究发现，常见的肠道细菌能促进前列腺癌的生长，并让它们规避治疗的影响。通过一种生长的雄激素或者雄性激素的替代来源，科学家们揭示了肠道细菌是如何促进晚期前列腺癌的发展以及对激素疗法的抗性。

激素疗法是晚期前列腺癌的护理标准，其作用是降低雄激素水平。但研究人员发现，患者体内低水平的雄激素会促进肠道细菌的繁殖，而这些肠道细菌会成为维持前列腺癌生长的激素工厂。

科学家确定的细菌“指纹”可以帮助识别出对治疗产生耐药性的高风险患者，这些患者可以从控制他们的“微生物群”的策略中受益。例如，男性饮用富含有益细菌的酸奶饮料。

来自伦敦癌症研究所、瑞士贝林佐纳肿瘤研究所和瑞士联邦理工学院的一组科学家利用小鼠和患者样本来研究肠道细菌在前列腺癌生长和发展中的作用。这些发现一旦在临床上得到进一步的验证，就会为通过控制微生物群来治疗前列腺癌提供新的机会。

肠道细菌是我们微生物群的一部分，通常对人类很有价值。然而，癌症和其他疾病可以破坏这种互利的平衡——例如，通过促进肠道细菌的增殖来促使它们释放毒素或其他影响癌细胞的分子。

基于这些“肠道细菌”在癌症中的作用，研究人员研究了前列腺癌患者的肠道细菌是否也会改变患者的激素代谢，从而影响癌症的生长。

科学家发现，清除前列腺癌小鼠体内的所有肠道细菌可以减缓肿瘤的生长，并延缓激素抵抗的出现。

他们还发现，将具有激素抵抗性前列腺癌小鼠的排泄物移植到雄激素水平较低但尚未产生耐药性的小鼠体内，也会促进肿瘤生长。

研究人员在小鼠身上证明了肠道细菌能够从前体分子中制造雄激素。为了将这一研究成果适用于人类，研究人员分析了在皇家马斯登NHS信托基金会医院接受治疗的患者的肠道细菌。他们观察了两组不同的患者——19名仍对激素治疗有反应的前列腺癌患者和55名激素抵抗性前列腺癌晚期患者。

将患有激素抵抗性前列腺癌的患者的排泄物移植到癌症无抗性的小鼠体内，促进了肿瘤生长和激素抗性。

科学家们还分析了前列腺癌患者排泄物中的微生物遗传物质，并确定了一种特定的细菌——瘤胃球菌，它可能在耐药性的发展中发挥了重要作用。相反，名为普雷沃氏菌的细菌与良好的临床结果相关。

基于前列腺癌患者的不同肠道细菌，研究人员培养出一种称为类器官的微型肿瘤，并试图在实验室中对其进行治疗。这有助于他们识别与前列腺癌预后相关的有利和不利的细菌“指纹”，这有利于确定哪些男性可以从控制微生物群的策略中受益。

伦敦癌症研究所实验癌症医学教授、皇家马斯登国民保健服务基金会的医疗肿瘤学顾问Johann de Bono教授说:“我们的研究发现，前列腺癌激素治疗的启动会触发“肠道细菌”开始产生雄激素。这些雄激素可以维持前列腺癌的生长，并导致对激素治疗的抵抗，从而恶化男性的生存结果。”

伦敦癌症研究所首席执行官Kristian Helin教授说:“肠道微生物对癌症的影响是一个迷人的新科学领域，我们才刚刚开始了解。这些令人兴奋的发现首次揭示了肠道微生物群驱动前列腺癌生长和激素治疗抗性的机制。了解肠道中常见的‘有益’细菌是如何干扰前列腺癌患者的激素代谢，有助于我们设计新的治疗策略。肠道细菌在保持我们健康方面发挥着重要作用。我期待着这项研究能应用于临床，并希望控制微生物群的策略能对患者产生真正的影响。”

肿瘤学研究所分子肿瘤学主任、帕多瓦大学和瑞士联邦理工学院教授Andrea Alimonti说:“我们的发现为辅助治疗策略铺平了道路，通过微生物菌体操作，对抗产生雄激素的细菌物种的扩张。”

英语原文

Gut Bugs Can Drive Prostate Cancer Growth and Treatment Resistance

Common gut bacteria can fuel the growth of prostate cancers and allow them to evade the effects of treatment, a new study finds. Scientists revealed how gut bacteria contribute to the progression of advanced prostate cancers and their resistance to hormone therapy—by providing an alternative source of growth-promoting androgens, or male hormones.

Hormone therapy is the standard of care for advanced prostate cancer and works by lowering levels of androgens. But researchers found that low androgen levels in patients can drive the expansion of gut bacteria, which can become hormone factories to sustain prostate cancer growth.

Bacterial ‘fingerprints’ identified by scientists may help pick out patients at high risk of developing resistance to treatment who could benefit from strategies to manipulate their ‘microbiome’. For example, men could take a yoghurt drink enriched with favourable bacteria.

A team of scientists from The Institute of Cancer Research, London, the Institute of Oncology Research in Bellinzona, Switzerland and the Swiss Federal Institute of Technology used mice and patient samples to investigate the role of gut bacteria in prostate cancer growth and progression.

The findings, once further validated in the clinic, could provide new opportunities for the treatment of prostate cancer through manipulation of the microbiome.

Gut bacteria are part of our microbiome and are usually valuable to humans. However, cancer and other diseases can ruin this mutually beneficial balance—for example by promoting the expansion of gut bacteria and encouraging them to release toxins or other molecules that affect cancer cells.

Given the role these ‘gut bugs’ can play in cancer, researchers looked at whether the gut bacteria from men with prostate cancer could also alter patients' hormone metabolism, and so affect cancer growth.

Scientists found that getting rid of all gut bacteria in mice with prostate cancer slowed tumour growth and delayed the emergence of hormone resistance.

They also found that transplanting faeces from mice with hormone-resistant prostate cancer into mice with low androgen levels that had not yet developed resistance encouraged tumour growth.

The researchers demonstrated in mice that gut bacteria were able to make androgen hormones from precursor molecules.

To translate the findings into humans, researchers analysed the gut bacteria from patients who were being treated at The Royal Marsden NHS Foundation Trust. They looked at two different groups of patients—19 men whose prostate cancers were still responding to hormone therapy and 55 men with advanced hormone-resistant prostate cancer.

Transplanting stool from prostate cancer patients with hormone-resistant prostate cancer into mice whose cancers were not resistant promoted tumour growth and hormone resistance.

Scientists also analysed microbial genetic material from the stool of men with prostate cancer and identified a specific bacterium—Ruminococcus – that may play a major role in the development of resistance. In contrast, the bacterium Prevotella stercorea was associated with favourable clinical outcomes.

Researchers incubated mini-tumours called organoids derived from prostate cancer patients with different gut bacteria and attempted to treat them in the lab. This helped them identify favourable and unfavourable bacterial ‘fingerprints’ linked to prostate cancer outcome, which could help identify men who could benefit from strategies to manipulate the microbiome.

Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said: "Our findings reveal that the initiation of hormone therapy for prostate cancer can trigger ‘gut bugs’ to start producing androgen hormones. These androgens can then sustain prostate cancer's growth and drive resistance to hormone therapy — worsening men's survival outcomes.

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said: "The influence of the gut microbiome on cancer is a fascinating new area of science that we are just beginning to understand. These exciting findings are the first to unveil a mechanism through which the gut microbiome can drive prostate cancer growth and resistance to hormone therapy.”

"Understanding how common, ‘good’ bacteria in the gut — which play a vital role in keeping us healthy — can interfere with hormone metabolism in men with prostate cancer could help us devise new treatment strategies. I look forward to this research moving forward into the clinic and hope that strategies to manipulate the microbiome could make a real difference for patients."

Professor Andrea Alimonti, Head of Molecular Oncology at the Institute of Oncology Research (IOR), Professor at Università della Svizzera italiana (USI), at the University of Padova and at the Swiss Federal Institute of Technology (ETH), said: "Our discoveries pave the way to adjuvant therapeutic strategies that, through microbiota manipulations, counteract the expansion of androgen-producing bacterial species."

参考文献

Nicolo Pernigoni et al, Commensal bacteria promote endocrine-resistance in prostate cancer via androgen biosynthesis, Science (2021).

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