Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition

Abstract

Although integrin alpha 2 subunit (ITGA2) mediates cancer progression and metastasis, its transfer by exosomes has not been investigated in prostate cancer (PCa). We aimed to determine the role of exosomal ITGA2 derived from castration-resistant PCa (CRPC) cells in promoting aggressive phenotypes in androgen receptor (AR)-positive cells. Exosomes were co-incubated with recipient cells and tested for different cellular assays. ITGA2 was enriched in exosomes derived from CRPC cells. Co-culture of AR-positive cells with CRPC-derived exosomes increased their proliferation, migration, and invasion by promoting epithelial-mesenchymal transition, which was reversed via ITGA2 knockdown or inhibition of exosomal uptake by methyl-β-cyclodextrin (MβCD). Ectopic expression of ITGA2 reproduced the effect of exosomal ITGA2 in PCa cells. ITGA2 transferred by exosomes exerted its effect within a shorter time compared to that triggered by its endogenous expression. The difference of ITGA2 protein expression in localized tumors and those with lymph node metastatic tissues was indistinguishable. Nevertheless, its abundance was higher in circulating exosomes collected from PCa patients when compared with normal subjects. Our findings indicate the possible role of the exosomal-ITGA2 transfer in altering the phenotype of AR-positive cells towards more aggressive phenotype. Thus, interfering with exosomal cargo transfer may inhibit the development of aggressive phenotype in PCa cells.

Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors

“…The expression of this mutant/ variant is decisive in determining the therapeutic approach for these patients [77] thus, determining EGFR status from exosomes instead of a tumor biopsy is of immense benefit for patients. Similar applications for exosomes have been described for ovarian cancer [73], melanoma [78] colorectal cancer [79], and prostate cancer [80,81]. Silva et al have reported that high levels of exosomes in plasma of patients with colorectal cancer were significantly associated with poorly differentiated tumors and with decreased overall survival (OS) [79] while patients with ovarian cancer exhibit significantly increased levels of serum exosomes compared to benign disease or healthy controls [73].…”

Integrin Regulation in Immunological and Cancerous Cells and Exosomes

“…For example, they have been linked to the progression of such neurodegenerative diseases as Alzheimer’s [ 87 ] and Parkinson’s diseases [ 88 ]. In particular, exosomes have been shown to participate in various steps of malignancy: tumor growth [ 89 ], tumor angiogenesis [ 90 ], inhibition of immunity [ 91 ] and metastasis [ 92 ]. The horizontal transfer of biological information, via exosomes, between cancer cells or between cancer cells and stromal cells/distant cells facilitates the creation of a pro-tumorigenic microenvironment [ 89 , 92 , 93 , 94 ].…”

“…The inherence of integrins from cells to exosomes has an impact on the biological functions of cancer and immune cells ( Figure 2 ). Exosomal integrins participate in multiple steps of cancer progression: they increase cell adhesion and migration, guiding cancer exosomes to specific metastatic sites (metastatic organotropism), preparing pre-metastatic niche formation, modulating the angiogenic potential of endothelial cells and activating the expression of certain genes (e.g., Src and the pro-inflammatory and pro-migratory S100 gene) [ 92 , 101 , 102 ]. Integrins exposed on exosomes engage with their specific ligands on target cells, and this interaction constitutes an important factor in the internalization of exosomes.…”

“…For example, the integrins α2, αVβ3 and αVβ6 can be propagated between different prostate cancer (PrCa) cells. After accepting integrins, recipient cells acquire more aggressive cancer phenotypes [ 89 , 92 , 93 , 94 , 104 ]. Obviously, exosomes can serve as chemoattractant signals for the extravasation of neutrophils into inflamed tissues.…”

“…The exosomal integrin transfer in prostate cancer has been well demonstrated in numerous studies. Androgen receptor-positive PrCa cells exhibit aggressive features, such as increasing their proliferation, migration and invasion upon transfer of exosomal integrin α2 from castration-resistant cells [ 92 ]. Integrin αVβ3, which is implicated in aggressive cancers, is expressed in exosomes released by metastatic PrCa cells (PC3 and CWR22Pc) and is horizontally transferred to non-tumorigenic BPH-1 cells or other tumorigenic C4-2B cells.…”