Papazoglou Eleftherios D, Jagirdar Rajesh M, Kouliou Olympia A, Pitaraki Eleanna, Hatzoglou Chrissi, Gourgoulianis Konstantinos I, Zarogiannis Sotirios G
Department of Physiology, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece.
Department of Respiratory Medicine, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece.
Cancers (Basel). 2019 Sep 27;11(10):1446. doi: 10.3390/cancers11101446.
Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The main treatment for MPM is doublet chemotherapy with Cisplatin and Pemetrexed, while ongoing trials test the efficacy of pemetrexed monotherapy. However, there is lack of evidence regarding the effects of Cisplatin and Pemetrexed on MPM cell phenotypes, especially in three-dimensional (3D) cell cultures. In this study, we evaluated the effects Cisplatin and Pemetrexed on cell viability using homologous cell derived extracellular matrix (hECM) as substratum and subsequently in the following 3D cell culture phenotypes: tumor spheroid formation, tumor spheroid invasion, and collagen gel contraction. We used benign mesothelial MeT-5A cells as controls and the MPM cell lines M14K (epithelioid), MSTO (biphasic), and ZL34 (sarcomatoid). Cell viability of all cell lines was significantly decreased with all treatments. Mean tumor spheroid perimeter was reduced after treatment with Pemetrexed or the doublet therapy in all cell lines, while Cisplatin reduced the mean spheroid perimeter of MeT-5A and MSTO cells. Doublet treatment reduced the invasive capacity of spheroids of cell lines into collagenous matrices, while Cisplatin lowered the invasion of the MSTO and ZL34 cell lines, and Pemetrexed lowered the invasion of MeT-5A and ZL34 cell lines. Treatment with Pemetrexed or the combination significantly reduced the collagen gel contraction of all cell lines, while Cisplatin treatment affected only the MeT-5A and M14K cells. The results of the current study can be used as an in vitro 3D platform for testing novel drugs against MPM for ameliorating the effects of first line chemotherapeutics.
恶性胸膜间皮瘤（MPM）是一种侵袭性癌症，预后较差。MPM的主要治疗方法是顺铂和培美曲塞联合化疗，同时正在进行的试验在测试培美曲塞单药治疗的疗效。然而，关于顺铂和培美曲塞对MPM细胞表型的影响，尤其是在三维（3D）细胞培养中的影响，缺乏相关证据。在本研究中，我们以同源细胞衍生的细胞外基质（hECM）为基质评估顺铂和培美曲塞对细胞活力的影响，并随后在以下3D细胞培养表型中进行评估：肿瘤球形成、肿瘤球侵袭和胶原凝胶收缩。我们使用良性间皮细胞MeT-5A作为对照，以及MPM细胞系M14K（上皮样）、MSTO（双向性）和ZL34（肉瘤样）。所有处理均使所有细胞系的细胞活力显著降低。培美曲塞或联合治疗后，所有细胞系的平均肿瘤球周长均减小，而顺铂降低了MeT-5A和MSTO细胞的平均球周长。联合治疗降低了细胞系的肿瘤球向胶原基质的侵袭能力，而顺铂降低了MSTO和ZL34细胞系 的侵袭，培美曲塞降低了MeT-5A和ZL34细胞系的侵袭。培美曲塞或联合治疗显著降低了所有细胞系的胶原凝胶收缩，而顺铂治疗仅影响MeT-5A和M14K细胞。本研究结果可作为一个体外3D平台，用于测试针对MPM的新型药物，以改善一线化疗药物的效果。
