Neoadjuvant Chemotherapy Shifts Breast Tumor Microbiota Populations to Regulate Drug Responsiveness and the Development of Metastasis.
Neoadjuvant Chemotherapy Shifts Breast Tumor Microbiota Populations to Regulate Drug Responsiveness and the Development of Metastasis.
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新辅助化学疗法会改变乳腺肿瘤微生物群体，以调节药物反应性和转移的发展。
DOI：
10.1158/1541-7786.mcr-19-0451
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发表时间：
2020-01
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乳腺肿瘤有自己的特殊微生物群，与正常乳腺组织不同。局部晚期乳腺癌患者通常在手术前接受新辅助化疗以减小肿瘤大小，从而保留乳房或限制腋窝淋巴结清扫。我们研究的目的是评估新辅助化疗是否调节肿瘤微生物组以及微生物对乳腺癌信号传导的潜在影响。使用快速冷冻无菌收集的乳腺肿瘤组织，从接受新辅助化疗的妇女（n=15）或在手术时没有先前治疗的妇女（n=18），我们进行了16S rRNA测序，以确定肿瘤细菌种群。我们还对乳腺肿瘤微阵列进行染色，以确认所鉴定的微生物群的存在。使用细菌条件培养基，我们确定了细菌代谢产物对乳腺癌细胞增殖和阿霉素治疗反应性的影响。我们表明化疗管理显着增加乳腺肿瘤假单胞菌。发生远处转移的患者的原发性乳腺肿瘤显示出短单胞菌和葡萄球菌的肿瘤丰度增加。我们通过免疫组化染色证实了假单胞菌在乳腺肿瘤组织中的存在。用铜绿假单胞菌条件培养基处理乳腺癌细胞以剂量依赖性方式差异性地影响增殖，并调节阿霉素介导的细胞死亡。我们的研究结果表明，化疗改变了乳腺肿瘤微生物组，特定微生物与肿瘤复发相关。对更大患者队列的进一步研究可能会更深入地了解微生物群在治疗结果中的作用，并开发出可以预测远处转移的新型细菌生物标志物。乳腺肿瘤微生物群通过治疗改变并影响分子信号传导。
Breast tumors have their own specific microbiota, distinct from normal mammary gland tissue. Breast cancer patients that present with locally advanced disease often undergo neoadjuvant chemotherapy to reduce tumor size prior to surgery to allow breast conservation or limit axillary lymph node dissection. The purpose of our study was to evaluate whether neoadjuvant chemotherapy modulates the tumor microbiome and the potential impact of microbes on breast cancer signaling. Using snap-frozen aseptically collected breast tumor tissue from women that underwent neoadjuvant chemotherapy (n=15) or women with no prior therapy at time of surgery (n=18), we performed 16S rRNA sequencing to identify tumoral bacterial populations. We also stained breast tumor microarrays to confirm presence of identified microbiota. Using bacteria-conditioned media, we determined the effect of bacterial metabolites on breast cancer cell proliferation and doxorubicin therapy responsiveness. We show chemotherapy administration significantly increased breast tumor Pseudomonas. Primary breast tumors from patients that developed distant metastases displayed increased tumoral abundance of Brevundimonas and Staphylococcus. We confirmed presence of Pseudomonas in breast tumor tissue by immunohistochemical staining. Treatment of breast cancer cells with Pseudomonas aeruginosa conditioned media differentially effected proliferation in a dose-dependent manner and modulated doxorubicin-mediated cell death. Our results indicate chemotherapy shifts breast tumor microbiome and specific microbes correlate with tumor recurrence. Further studies with a larger patient cohort may provide greater insights into the role of microbiota in therapeutic outcome and develop novel bacterial biomarkers that could predict distant metastases. Breast tumor microbiota are modified by therapy and affects molecular signaling.