Adipose Tissue-Derived Extracellular Vesicles Contribute to Phenotypic Plasticity of Prostate Cancer Cells

Abstract

Metastatic prostate cancer is one of the leading causes of male cancer deaths in the western world. Obesity significantly increases the risk of metastatic disease and is associated with a higher mortality rate. Systemic chronic inflammation can result from a variety of conditions, including obesity, where adipose tissue inflammation is a major contributor. Adipose tissue endothelial cells (EC) exposed to inflammation become dysfunctional and produce a secretome, including extracellular vesicles (EV), that can impact function of cells in distant tissues, including malignant cells. The aim of this study was to explore the potential role of EVs produced by obese adipose tissue and the ECs exposed to pro-inflammatory cytokines on prostate cancer phenotypic plasticity in vitro. We demonstrate that PC3ML metastatic prostate cancer cells exposed to EVs from adipose tissue ECs and to EVs from human adipose tissue total explants display reduced invasion and increased proliferation. The latter functional changes could be attributed to the EV miRNA cargo. We also show that the functional shift is TWIST1-dependent and is consistent with mesenchymal-to-epithelial transition, which is key to establishment of secondary tumor growth. Understanding the complex effects of EVs on prostate cancer cells of different phenotypes is key before their intended use as therapeutics.