Ovarian cancer is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in ovarian cancer. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the ovarian cancer tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast–derived IL6 was proven to mediate ovarian cancer tumor cell chemoresistance. For the first time, we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in ovarian cancer. Mol Cancer Ther; 17(6); 1291–302. ©2018 AACR.

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二甲双胍通过灭活卵巢癌中的基质成纤维细胞来抑制肿瘤进展

卵巢癌是一种毁灭性的疾病，因为它的复发率和化学抗药性很高。肿瘤微环境，尤其是肿瘤基质区室，被证明是导致卵巢癌化疗效果不理想的原因。细胞毒剂不仅影响肿瘤细胞，还调节大量基质细胞群的表型和特征，进而改变肿瘤细胞对化学干预的反应。在这项研究中，我们专注于肿瘤基质对细胞毒剂的反应以及对卵巢癌肿瘤细胞的后续影响。首先，我们发现接受基于顺铂治疗的患者样本中 IL6 的显着基质过表达，这在用顺铂激发的纯化成纤维细胞中得到了进一步验证。基质成纤维细胞来源的 IL6 被证明可介导卵巢癌肿瘤细胞的化学抗性。我们首次发现常规二甲双胍给药患者的肿瘤基质表现出较低的 IL6 表达。因此，我们推测二甲双胍是卵巢癌间质炎症的有效缓解剂。我们发现二甲双胍部分逆转了基质成纤维细胞中顺铂刺激的 IL6 分泌，并减弱了 3D 器官共培养和鼠异种移植模型中成纤维细胞促进的肿瘤生长。从机制上讲，我们发现二甲双胍通过抑制 NFκB 信号传导来抑制 IL6 分泌，NFκB 信号是基质炎症的上游控制器。总的来说，我们的研究结果介绍了二甲双胍通过减少化疗诱导的基质激活来抑制卵巢癌进展的新机制。因此，我们提供了一种针对基质炎症的替代治疗选择，并提供了一种潜在的联合治疗方案，以提高卵巢癌的化学敏感性。摩尔癌症治疗; 17(6); 1291-302。©2018 AACR。