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Abstract
Epithelial ovarian cancer (EOC) is a devastating disease, which accounts for a large proportion of gynaecological cancer-related deaths. Poor survival is largely due to late diagnosis of the disease, typically with tumour dissemination. In order to reduce tumour burden and improve survival, it is imperative to identify prognostic markers and therapeutic targets. High ABCA1 expression has been associated with poor outcome in EOC. While ABCA1 has been well studied as a cholesterol transporter, there is little research investigating its potential roles in cancer biology. This work addresses the biological contribution of ABCA1 in promoting aggressive characteristics of EOC, in addition to characterising five EOC cell lines cultured using 3D-culture models.
Assessment of EOC cell lines cultured by two independent 3D-culture techniques revealed the varying ability to form compact spheroids and contrast in proliferative capacity and anoikis resistance between the EOC cell lines. No strong correlation was observed between molecular properties and spheroid formation, proliferation or anoikis; however, comparison between monolayer and the 3D-culture models revealed differences in protein expression levels and activity states of signalling proteins commonly associated with cancer development and progression.
To address the biological role of ABCA1 in EOC, malignant properties were assessed in monolayer and 3D-spheroid culture assays. ABCA1 suppression in EOC cell lines led to reduced colony forming ability and migration by comparison with controls. Furthermore, ABCA1 suppression significantly reduced monolayer growth and spheroid volume, which was associated with increased apoptosis in 27/87 cells, whilst corresponding to reduced proliferation in HEY cells. It was further observed that ABCA1 suppression reduced spheroid compaction of EOC cell lines and dramatically impaired the development of a necrotic core in HEY spheroids, which is typically a prominent feature of the HEY spheroid architecture. Compaction and core necrosis are both well-documented processes in spheroid biology that are indicative of cellular contractility and a hypoxic tumour environment, both key characteristics of more aggressive, chemo-resistant and recurrent tumours. Collectively these data suggest that ABCA1 may be involved in regulating multiple processes associated with aggressive characteristics of EOC, highlighting ABCA1 as a potential therapeutic target.