Department of Pathology, University of Michigan, Ann Arbor, Michigan.
Department of Gynecology, The Third Xiangya Hospital, Central South University, Changsha, China.
Cancer Res. 2021 Jun 15;81(12):3309-3318. doi: 10.1158/0008-5472.CAN-21-0106. Epub 2021 Apr 16.
Studies have shown bacteria influence the initiation and progression of cancers arising in sites that harbor rich microbial communities, such as the colon. Little is known about the potential for the microbiome to influence tumorigenesis at sites considered sterile, including the upper female genital tract. The recent identification of distinct bacterial signatures associated with ovarian carcinomas suggests microbiota in the gut, vagina, or elsewhere might contribute to ovarian cancer pathogenesis. Here, we tested whether altering the microbiome affects tumorigenesis in a mouse model of high-grade serous carcinoma (HGSC) based on conditional oviduct-specific inactivation of the , , , and tumor suppressor genes. Cohorts of control ( = 20) and antibiotic-treated ( = 23) mice were treated with tamoxifen to induce tumor formation and then monitored for 12 months. The antibiotic cocktail was administered for the first 5 months of the monitoring period in the treatment group. Antibiotic-treated mice had significantly fewer and less advanced tumors than control mice at study endpoint. Antibiotics induced changes in the composition of the intestinal and vaginal microbiota, which were durable in the fecal samples. Clustering analysis showed particular groups of microbiota are associated with the development of HGSC in this model. These findings demonstrate the microbiome influences HGSC pathogenesis in an model that closely recapitulates the human disease. Because the microbiome can modulate efficacy of cancer chemo- and immunotherapy, our genetically engineered mouse model system may prove useful for testing whether altering the microbiota can improve the heretofore poor response of HGSC to immunotherapies. SIGNIFICANCE: This study provides strong evidence for a role of the microbiome in ovarian cancer pathogenesis.
研究表明，在富含微生物群落的部位（如结肠），细菌会影响癌症的发生和发展。目前人们对微生物组在被认为无菌的部位（包括女性上生殖道）影响肿瘤发生的潜力知之甚少。最近发现与卵巢癌相关的独特细菌特征表明，肠道、阴道或其他部位的微生物群可能有助于卵巢癌的发病机制。在这里，我们测试了改变微生物组是否会影响基于条件输卵管特异性失活的高级别浆液性卵巢癌（HGSC）小鼠模型中的肿瘤发生。对照组（=20）和抗生素处理组（=23）的队列接受他莫昔芬治疗以诱导肿瘤形成，然后监测 12 个月。在治疗组的监测期的前 5 个月给予抗生素鸡尾酒。与对照组相比，抗生素处理组的小鼠在研究终点时的肿瘤数量明显更少，进展程度也更低。抗生素诱导了肠道和阴道微生物群组成的变化，这些变化在粪便样本中是持久的。聚类分析表明，某些微生物群与该模型中 HGSC 的发生有关。这些发现表明，微生物组会影响这种模型中 HGSC 的发病机制。由于微生物组可以调节癌症化疗和免疫治疗的疗效，我们的基因工程小鼠模型系统可能有助于测试改变微生物组是否可以改善 HGSC 对免疫疗法的反应不良。意义：本研究为微生物组在卵巢癌发病机制中的作用提供了强有力的证据。
