转化生长因子β信号通路调节卵巢癌腹水来源球体中的上皮-间质可塑性。
TGFβ signaling regulates epithelial-mesenchymal plasticity in ovarian cancer ascites-derived spheroids.
作者信息
Rafehi Samah, Ramos Valdes Yudith, Bertrand Monique, McGee Jacob, Préfontaine Michel, Sugimoto Akira, DiMattia Gabriel E, Shepherd Trevor G
机构信息
Translational Ovarian Cancer Research ProgramLondon Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, Ontario, Canada N6A 4L6Department of Anatomy and Cell BiologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of BiochemistrySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of Obstetrics and GynaecologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of OncologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada Translational Ovarian Cancer Research ProgramLondon Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, Ontario, Canada N6A 4L6Department of Anatomy and Cell BiologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of BiochemistrySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of Obstetrics and GynaecologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of OncologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
Translational Ovarian Cancer Research ProgramLondon Regional Cancer Program, 790 Commissioners Road East, Room A4-836, London, Ontario, Canada N6A 4L6Department of Anatomy and Cell BiologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of BiochemistrySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of Obstetrics and GynaecologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, CanadaDepartment of OncologySchulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
出版信息
Endocr Relat Cancer. 2016 Mar;23(3):147-59. doi: 10.1530/ERC-15-0383. Epub 2015 Dec 8.
Epithelial-mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFβ) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFβ signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up-regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFβ type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFβ signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease.
上皮-间质转化（EMT）是驱动多种癌症中肿瘤细胞迁移、侵袭和转移的关键机制。转化生长因子-β（TGFβ）信号传导参与癌症发病过程中的多个步骤，是EMT的经典诱导因子。由于上皮性卵巢癌（EOC）细胞在转移过程中具有在上皮和间质状态之间转换的潜力，我们预测TGFβ信号传导的调节将显著影响EMT和EOC球状体细胞的恶性潜能。卵巢癌患者腹水来源的细胞在聚集成球状体时自然会发生EMT反应，而当球状体重新附着于基质时，这种反应会逆转。与贴壁细胞相比，球状体中CDH1/E-钙黏蛋白的表达明显降低，同时几种转录抑制因子，即SNAI1/蜗牛、TWIST1/2和ZEB2上调。用TGFβI型受体抑制剂SB-431542处理EOC球状体，可有效阻断球状体中EMT的内源性激活。此外，在重新附着后用SB-431542处理球状体可增强分散细胞的上皮表型，并显著降低细胞运动性和Transwell迁移。暴露于SB-431542会显著损害球状体的形成，这与细胞活力降低相关，尤其是与卡铂联合治疗时。因此，我们的研究结果首次证明，完整的TGFβ信号传导是控制EOC腹水来源的细胞球状体中EMT所必需的，并且它促进了这些结构的恶性特征。因此，我们展示了在晚期卵巢癌患者中靶向抑制该途径的治疗潜力。
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