Endometrial cancer (EC) arises from the lining of the uterus and is the most common gynaecological malignancy in Aotearoa New Zealand. Its incidence has doubled over the past decade, with more than 750 new diagnoses annually. The most common subtype, endometrioid EC, is strongly associated with metabolic disorders such as obesity and Type II diabetes. Insulin resistance and hyperglycaemia promote endometrial proliferation and malignant transformation.
Given the established role of extracellular vesicles (EVs) in intercellular communication, we hypothesised that hyperglycaemia alters EV production, cargo, and function in EC. To investigate this, we cultured three EC cell lines in 3D CELLine bioreactors under high-glucose conditions to model the diabetic tumour microenvironment. Small (sEV) and large (lEV) EVs were analysed for protein content and their effects on Ishikawa cell phenotypes, including proliferation, ATP activity, anchorage-independent colony formation, and collagen adhesion.
sEV production under high-glucose conditions varied across cell lines, indicating a cell line–specific response. Proteomic analysis revealed that the most prominent differences in EV cargo were between cell lines, with more subtle but consistent glucose-dependent enrichments in pathways related to matrix remodelling and metabolism. Functional assays showed no significant differences between EVs from high- vs normal-glucose conditions. However, sEVs from all 3 EC cell lines reduced colony formation, while lEVs promoted collagen adhesion, suggesting distinct roles in modulating cellular behaviour.
Ongoing pathway-guided functional assays will further clarify the role of EVs in manipulating the microenvironment in hyperglycaemia-associated endometrial cancers.