Abstract
Simple SummaryEpithelial Ovarian Cancer is considered to be a ‘silent killer’ and a challenge for gynaecological health across the world due to its asymptotic nature in the early stages, its late-stage diagnosis, high recurrence rate and resistance to currently available treatment methods (chemotherapy). These disheartening figures highlight the need for extensive in vitro studies to better understand this disease. A number of in vitro 3D models are currently available to aid in the study of ovarian cancer and its response to therapeutic methods. In this work, we report, for the first time, a comprehensive comparative study of three widely used 3D in vitro models for ovarian cancer, along with chemotherapy assessment of primary and metastatic cells. Our study highlights the importance of selecting an appropriate 3D in vitro platform, which is based on multiple factors including the origin of cells used, experimental time period and experimental design, even for one specific disease.Epithelial Ovarian Cancer (EOC) is a silent, deadly and aggressive gynaecological disease with a relatively low survival rate. This has been attributed, to some extent, to EOC’s high recurrence rate and resistance to currently available platinum-based chemotherapeutic treatment methods. Multiple groups have studied and reported the effect of chemotherapeutic agents on various EOC 3D in vitro models. However, there are very few studies wherein a direct comparative study has been carried out between the different in vitro 3D models of EOC and the effect of chemotherapy within them. Herein, we report, for the first time, a direct comprehensive systematic comparative study of three different 3D in vitro platforms, namely (i) spheroids, (ii) synthetic PeptiGels/hydrogels of various chemical configurations and (iii) polymeric scaffolds with coatings of various extracellular matrices (ECMs) on the cell growth and response to the chemotherapeutic (Cisplatin) for ovary-derived (A2780) and metastatic (SK-OV-3) EOC cell lines. We report that all three 3D models are able to support the growth of EOC, but for different time periods (varying from 7 days to 4 weeks). We have also reported that chemoresistance to Cisplatin, in vitro, observed especially for metastatic EOC cells, is platform-dependent, in terms of both the structural and biochemical composition of the model/platform. Our study highlights the importance of selecting an appropriate 3D platform for in vitro tumour model development. We have demonstrated that the selection of the best platform for producing in vitro tumour models depends on the cancer/cell type, the experimental time period and the application for which the model is intended.
Highlights
Epithelial Ovarian Cancer (EOC) is the seventh most common cancer amongst women across the world and the third most common gynaecological cancer, ranked after cervical and uterine [1]
A 2780 cell line was derived from the ovarian tumour of an untreated patient while SK-OV-3 was derived from the ascites fluid post-metastasis
Cisplatin, a widely used chemotherapeutic agent for EOC [35,44], roidsintroduced on day 7 to of the culture at afor concentration of 50. Was culture medium both A2780 and SK-OV-3 on day Thereafter, Cisplatin-containing medium was replaced with fresh medium and the spheof culture [40,44] at a concentration of 50 μM for 48 h [38] (Section 2.4)
Summary
Epithelial Ovarian Cancer (EOC) is the seventh most common cancer amongst women across the world and the third most common gynaecological cancer, ranked after cervical and uterine [1]. It has been observed that over 80% of patients have a relapse post chemotherapy, along with the development of a platinum-resistant aggressive form of EOC, all of which can be attributed, to a large extent, to EOC’s complex tumour microenvironment (TME) [10–13] The latter is a cocktail of different cellular, structural, biochemical (extracellular matrix (ECM) protein composition), biophysical and biomechanical features, all of which interact in complex and sometimes unknown ways with the tumour, leading to its progression, resistance to treatment and metastasis. Overall, these disheartening data suggest that there is an unmet need for ex vivo models of EOC in order to better understand the disease, EOC’s complex TME and its unique mode of metastasis, as well as to predict patient-specific, personalised drug responses
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