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.

EV-miRNA-Mediated Intercellular Communication in the Breast Tumor Microenvironment

“…The most recent study by Mathiesen et al, determine the contribution of omental (OM) and subcutaneous (SC) adipose tissue EVs (ATEVs) in metastatic prostate cancer (PC3ML cells) and evaluated the miRNA cargo with NanoString array. Forty-eight miRNAs were detected in SC ATEVs, 55 in OM ATEVs and 44 in both; transcriptomic analyses on PC3ML after treatment with ATEVs showed differentially expressed genes associated with proliferation, invasion and glycolysis and were validated with functional assays [98].…”

Extracellular vesicles in neuroblastoma: role in progression, resistance to therapy and diagnostics

“…Interestingly, besides the TEV-mediated signaling, several recent studies have identified the role of stromal cell-derived EVs in supporting cancer progression by affecting the tumor cells, thus indicating a bidirectional EV-mediated crosstalk in cancer. EVs derived from adipocytes and adipose-endothelial cells were found to induce proliferation, migration and invasion of the recipient prostate cancer cells, thereby promoting metastasis in prostate cancer ( 64 , 65 ). While CAFs were found to support the surrounding tumor cells by transferring tumor-supportive signals via EVs, thereby contributing to tumor growth and metastasis in several cancer types ( 62 , 66 – 68 ).…”

Research advances of tissue-derived extracellular vesicles in cancers

“…Mathiesen found that PC3ML metastatic prostate cancer cells proliferated significantly after contacting with EVs from adipose tissue. This may be attributed to the transcription factor twist family bHLH transcription factor 1 (twist1), which is critical for secondary tumor growth (Mathiesen et al 2023 ).…”

“…Adipose Ti-EVs derived from overweight and obese people increased melanoma migration compared with those from the lean individuals (Lazar et al 2015 ). miRNAs contained in adipose Ti-EVs, such as miR-128 and miR-155, were also found to promote cancer invasion and metastasis, especially in a pro-inflammatory environment (Mathiesen et al 2023 ). Moraes found that ADSC-derived EVs may activate the Janus kinase (JAK)/signal transducer and activator of transcription (STAT-3) pathway through epidermal growth factor receptor 1 (EGFR-1)/IL-6, thereby promoting breast cancer cell migration and metastasis (Moraes et al 2021 ).…”

“…The tumor Ti-EVs have been used together with body fluid EVs for cancer early diagnosis, monitoring of treatment response, and analysis of unknown primary tumors (Hoshino et al 2020 ; Tomiyama et al 2021 ; Maruoka et al 2022 ). Adipocytes are an important part of the tissue surrounding the tumor and adipose Ti-EVs were found to have widespread effects on tumors by providing metabolic substrates to support their progression and metastasis (Liu et al 2023 ; Mathiesen et al 2023 ). Exploring the role of adipose Ti-EVs in tumorigenesis and development can offer new strategies for tumor detection and treatment.…”