The effects of size and shape of the ovarian cancer spheroids on the drug resistance and migration

• Published in: Gynecologic oncology 2020-11, Vol.159 (2), p.563-572
• Main Authors: Gunay, Gokhan, Kirit, Hande A., Kamatar, Advika, Baghdasaryan, Ofelya, Hamsici, Seren, Acar, Handan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Carcinoma, Ovarian Epithelial - drug therapy; Carcinoma, Ovarian Epithelial - genetics; Cell Movement; Cisplatin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - drug effects; Epithelial to mesenchymal transition; Female; Gene Expression Regulation, Neoplastic; Humans; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Paclitaxel - pharmacology; Spheroid; Spheroids, Cellular - pathology; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - pathology
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2020.09.002

High fatality in ovarian cancer is attributed to metastasis, propagated by the release of multi-cellular aggregates/spheroids into the peritoneal cavity and their subsequent mesothelial invasion of peritoneal organs. Spheroids are therefore a common and clinically relevant in vitro model for ovarian cancer research. Spheroids in patients vary significantly in size and shape and display enhanced resistance to anti-cancer drugs compared to monolayers. However, there is no consensus on how spheroid size and shape affect drug resistance. Moreover, existing data regarding the influence of epithelial-to-mesenchymal transition (EMT) profile on spheroid shape and migration is inconclusive. We formed spheroids with OVCAR-3 and OVCAR-8 cells, chosen for their established genetic similarity to the patient tumor samples. We monitored their morphology using confocal microscope with dipping objective and fluorescent microscope. We characterized important EMT biomarkers; E-cadherin, Vimentin and Slug through western blotting in monolayers and spheroids. We treated these spheroids with Taxol and Cisplatin and investigated their migratory profile based on their morphology. We report two distinct multicellular structures: loose aggregates (OVCAR-3) and compact spheroids (OVCAR-8). We attribute these different morphologies to the expression of the EMT biomarkers, and their changes upon spheroid formation. Importantly, we did not observe a difference in resistance to the anti-cancer drugs as a function of spheroid size and shape. However, migration capacity of compact spheroid (OVCAR-8) was 15-fold higher compared to that of loose aggregates (OVCAR-3). These results highlight the importance of spheroid size and shape on anti-cancer drug resistance and migration profiles. The results of this study can, therefore, help to elucidate general rules for ovarian cancer studies based on 3D samples. Formation of loose aggregates and compact spheroids using OVCAR-3 and OVCAR-8 cells, respectively. [Display omitted] •High-throughput formation of ovarian cancer spheroids in different sizes.•Observation of EMT biomarkers (E-cadherin, Vimentin, Slug) in different spheroid morphologies.•Observation of the effect of spheroid size and shape on anti-cancer drug resistance.•Influence of the shape of the spheroids on their migratory profile.