Extracellular vesicles as drivers of epithelial‐mesenchymal transition and carcinogenic characteristics in normal prostate cells

Abstract

There is increasing evidence that cancer dissemination and metastasis establishment may not only be due to the movement of tumor cells. Content of extracellular vesicles (EVs) secreted by tumor cells may also reflect the origin of these cells. Some molecules that constitute these EVs have already been used as targets for detection of specific tumors. However, to the best of our knowledge, EVs from biopsies and plasma have not yet been compared nor thoroughly investigated as triggers of malignant transformation and metastatic niche formation. To evaluate the role of EVs in the cellular microenvironment, we have treated the normal epithelial prostate cell lines, RWPE-1 and PNT-2, with a pool of EVs from biopsies of prostate primary tumors (bEVs), biopsies of benign prostate hyperplasia (hEVs), plasma of prostate cancer (PCa) patients (pEVs) or plasma of healthy individuals (pnEVs). Each of the four pools consisted of isolated EVs from several subjects, of which PCa patients were in different stages of cancer. Migration and proliferation profiles, cytokine release, and a panel of PCa-associated genes' expression of epithelial-mesenchymal transition in the cell lines were evaluated after 24 h incubation with EVs. When compared to the control groups, cells treated with the pool of EVs isolated from tumor biopsies and plasma of PCa patients showed greater migration and proliferation, significant alterations in gene expression, and high levels of IL-8, factors that are associated with cancer development. Specifically, isolated bEVs and pEVs may induce malignant features in non-tumor cells by activating several cellular events associated with cancer progression, suggesting that future PCa therapy may target multiple elements found in tumor-derived EVs.

Extracellular Vesicles in Prostate Cancer Carcinogenesis, Diagnosis, and Management

“…Tumors developed that were bigger when EVs were previously injected in rat prostates, in relation with a higher macrophage infiltration but also with an increased proliferation of rat normal epithelial cells ( 131 ). In other studies, normal epithelial prostate cell lines RWPE-1 and PNT-2 and prostate cancer cell lines LNCaP and DU-145 were exposed to EVs derived from the supernatants of primary cultures of PCa and BPH tissues as well as EVs extracted from plasma of PCa patients and healthy controls ( 132 ) or to exosomes extracted from LNCaP and DU-145 cells ( 133 ). Significant changes were observed in treated cells such as decreased apoptosis, increased migration and proliferation, increased secretion of interleukin-8 [a proinflammatory chemokine associated with the promotion and progression of several cancers ( 134 )], alterations in gene expression suggestive of EMT ( 132 , 133 ).…”

“…In other studies, normal epithelial prostate cell lines RWPE-1 and PNT-2 and prostate cancer cell lines LNCaP and DU-145 were exposed to EVs derived from the supernatants of primary cultures of PCa and BPH tissues as well as EVs extracted from plasma of PCa patients and healthy controls ( 132 ) or to exosomes extracted from LNCaP and DU-145 cells ( 133 ). Significant changes were observed in treated cells such as decreased apoptosis, increased migration and proliferation, increased secretion of interleukin-8 [a proinflammatory chemokine associated with the promotion and progression of several cancers ( 134 )], alterations in gene expression suggestive of EMT ( 132 , 133 ). Of note, observed effects differed according to both parental and target cells: LNCaP-derived exosomes had lower effect than DU-145-derived exosomes, while apoptosis was only reduced in LNCaP and proliferation was only increased in LNCaP and DU-145 cells and not RWPE-1 cells ( 133 ).…”

Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells

“…Data in the literature show that ovarian cancer-derived EVs activate normal fibroblast into a cancer-associated fibroblast phenotype, capable of sustaining tumour growth [46]. Moreover, it has been shown that prostate cancer-derived EVs can drive epithelial-mesenchimal transition in normal prostate cells [47]. It has also been reported that exosomes, isolated from the murine prostate cancer cell line TRAMP-C1, are involved in tumour and bone cell interactions [48].…”

Exosomes are the Driving Force in Preparing the Soil for the Metastatic Seeds: Lessons from the Prostate Cancer

“…Soekmadji et al reported that the increase in androgen-deprived LNCaP cell proliferation was correlated with the release of CD9-positive exosomes [87]. Another study showed that LNCaPand DU-145-derived exosomes can induce cell proliferation, epithelial-mesenchymal transition (EMT), migration, and IL-8 secretion while decreasing apoptosis in PCa cells [88][89][90]. In addition, hypoxic PCa cell-derived exosomes convey information that can be directly involved in the invasiveness and motility of dormant PCa cells [91].…”