Abstract
Approximately 10% of all cancer diagnoses in Aotearoa, New Zealand are gynaecological. Maori and Pacific populations within Aotearoa are disproportionately impacted by gynaecological cancers. Of the gynaecological cancers, ovarian cancer is of special concern. Although the incidence of ovarian cancer has been declining in the developed world, it is still the leading cause of gynaecological cancer mortality in Aotearoa, and it is Maori and Pacific who fare the worst. Women with ovarian cancer are often diagnosed at a late stage when standard treatment of debulking surgery and chemotherapy has poor clinical outcomes. Therefore, investigating treatment strategies that have the potential to reduce ovarian cancer mortality are justified.
Advanced ovarian cancer is characterised by tumour cells aggregating within ascitic fluid and embedding on distal organs. Ascitic fluid is rich in cytokines, growth factors, and phospholipids essential for secondary tumour establishment and growth. Tumour necrosis factor-alpha (TNF-α) and lysophosphatidic acid (LPA) are critical components that modulate ovarian tumour cell behaviour, but most in vitro studies have relied on cell monolayers that poorly represent the tumour microenvironment. The first aims of this thesis were therefore to optimise a more relevant in vitro 3D ovarian cancer model, and to test the impact of TNF-α and LPA on cell behaviour.
A 3D collagen model was selected to represent a newly established ovarian cancer metastasis. Four ovarian cancer cell lines, SKOV3, OVCAR8, OVCAR5 and OVCAR4, were selected to optimise the collagen gel model, and examine their malignant behavioural response to different FBS concentrations, different time points (up to 6 days of culture), and the presence of TNF-α or LPA. An optimised 3 D model was developed and data demonstrated TNF-α- and LPA-cell line specific effects on ovarian cancer cells in 3D collagen models, highlighting the utility of the 3D model and heterogeneity of the cell lines.
A prominent cell signalling pathway in ovarian cancer, and upregulated by TNF-α and LPA, is the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) pathway. As such, the next aim of this thesis was to investigate the effects of three PI3K inhibitors, pan PI3K inhibitor buparlisib, targeted PI3Kα inhibitor SN32976 and natural compound pterostilbene, in an optimised ovarian 3D collagen gel model of SKOV3 and OVCAR8 in the presence of TNF-α or LPA. Data showed that SN32976 and pterostilbene were able to attenuate the malignant behaviour of SKOV3 induced by LPA.
The final aim was undertaken with a Pacific in Aotearoa equity lens. Therefore, a nationwide survey of ‘Knowledge and perception of gynaecological cancers by Pacific women in Aotearoa’ was conducted simultaneously with laboratory investigations. Analysis of the survey revealed that there is a need for culturally responsive gynaecological cancer education, with cost of treatment as well as quality of life being top priorities for Pacific women.
In conclusion, potentially more cost-effective treatments with the possibility of improving quality of life for patients with ovarian cancer, such as SN32976 and pterostilbene, warrant further investigation as equitable treatments. Furthermore, the co-design of educational resources addressing gynaecological cancers may improve health equity in Aotearoa.