Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Obstetrics and Gynecology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Mol Cancer Ther. 2018 Jun;17(6):1291-1302. doi: 10.1158/1535-7163.MCT-17-0927. Epub 2018 Mar 15.
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. .
卵巢癌是一种毁灭性疾病，因为其复发率和化疗耐药率很高。肿瘤微环境，尤其是肿瘤基质隔室，已被证明对卵巢癌化疗效果不理想有巨大贡献。细胞毒性药物不仅作用于肿瘤细胞，还能调节庞大基质细胞群体的表型和特征，而这反过来又会改变肿瘤细胞对化疗干预的反应。在这项研究中，我们专注于肿瘤基质对细胞毒性药物的反应，以及随后对卵巢癌细胞的影响。首先，我们发现接受顺铂治疗的患者样本中基质细胞过度表达 IL6，这在接受顺铂挑战的纯化成纤维细胞中得到了进一步验证。证明源自基质成纤维细胞的 IL6 介导了卵巢癌肿瘤细胞的化疗耐药性。我们首次发现，常规给予二甲双胍的患者肿瘤基质中 IL6 的表达较低。因此，我们推测二甲双胍是卵巢癌基质炎症的有效缓解剂。我们发现二甲双胍部分逆转了顺铂刺激的基质成纤维细胞中 IL6 的分泌，并减弱了 3D 器官型共培养和小鼠异种移植模型中基质成纤维细胞促进的肿瘤生长。在机制上，我们发现二甲双胍通过抑制 NFκB 信号通路抑制 IL6 的分泌，NFκB 信号通路是基质炎症的上游调控因子。总的来说，我们的研究结果介绍了二甲双胍通过抑制化疗引起的基质激活来抑制卵巢癌进展的新机制。因此，我们为靶向基质炎症提供了一种替代治疗选择，并为提高卵巢癌的化疗敏感性提供了一种潜在的联合治疗方案。
