Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer

Abstract

Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaPabl), transgenic mice (Pb-Cre4;Ptenflox/flox;Rosa26ERG/ERG) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.

Potential Role of Exercise Induced Extracellular Vesicles in Prostate Cancer Suppression

“…The study by Albino et al (29) also generated a castrationresistant cell model using the LNCaP cell line by culturing in an androgen-depleted condition and showed significantly increased miR-424 in castration-resistant LNCaP-derived EVs compared to EVs derived from normal LNCaP cells (P<0.005), confirming the elevation in circulating miR-424 positive EVs in patients with advanced PCa (29). Furthermore, the application of EVs isolated from the castrate-resistant LNCaP-derived EVs to another PCa cell line, RWPE-1, showed increased tumor formation in a 3D cell culture model and cell migration compared to the application of normal LNCaP cell-derived EVs (P<0.005) (29), confirming the result by applying human plasma isolated EVs to cancer cell lines.…”

“…Recently, extracellular vesicles have been highlighted in cellto-cell and cell-to-extracellular matrix communications, and in PCa tumor-derived EVs have been suggested as a therapeutic target (24)(25)(26). Tumor-derived EVs have potential in delivering oncogenic proteins, surface proteins, and miRNAs to non-tumor cells and contribute to progression of PCa by initiating growthpromoting signal cascades or creating metastatic niches among non-tumoral cells near cancerous cells (29,31,33,34). As such, multiple proteins, miRNAs, and surface proteins in tumorderived EVs have been identified as potential predictable markers for PCa progression (22,23,26).…”

“…The study by Albino and colleagues ( 29 ) investigating the role of circulating miR-424 positive EVs in PCa patients demonstrated that metastatic PCa patients (metastatic castration-sensitive (mCSPC), n=16; metastatic castration-resistance (mCRPC), n=17) showed a higher frequency ( P <0.05) of circulating miR-424 positive EVs compared to patients with primary tumors (n=25) and benign prostatic hyperplasia (BPH, n=6). Moreover, the application of EVs isolated from plasma of patients (n=17) in the in vitro environment showed increased tumor-sphere formation in the application of EVs from patients with mCSPC and mCRPC compared to primary or BPH patients ( P <0.02) ( 29 ). In addition, the level of miR-424 containing EVs was positively associated with tumor growth in the 3D cell culture environment (tumor-sphere formation) ( P =0.003) ( 29 ), suggesting a potential role of EV-contained miRNAs in PCa progression.…”

“…Moreover, the application of EVs isolated from plasma of patients (n=17) in the in vitro environment showed increased tumor-sphere formation in the application of EVs from patients with mCSPC and mCRPC compared to primary or BPH patients ( P <0.02) ( 29 ). In addition, the level of miR-424 containing EVs was positively associated with tumor growth in the 3D cell culture environment (tumor-sphere formation) ( P =0.003) ( 29 ), suggesting a potential role of EV-contained miRNAs in PCa progression.…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 5: Epigenetic Regulation of PD-L1

“…Recently, some authors reported that patients with advanced PC release fully functional circulating extracellular vesicles containing miR-424, which facilitate the acquisition of stem-like traits by low tumorigenic cells, favoring metastatic behavior and cancer progression; circulating miR-424-expressing extracellular vesicles were more frequent in patients with metastatic PCs [212][213][214].…”