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

Rofaida Gaballa,Hamed I Ali,Heba F Salem,Mohamed A Kandeil,Johng S Rhim,Mohammad Saleem,Stefan Ambs,Mohamed O Mahmoud,Hamdy E A Ali,Zakaria Y Abd Elmageed

doi:10.3390/cancers12082300

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.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among elder men [1]. prostate cancer (PCa) is a multifactorial disease, androgen and its receptor (AR) represent the main driving force for PCa progression
We found that integrin alpha 2 subunit (ITGA2) was enriched in exosomes of castration-resistant PCa (CRPC) versus androgen receptor (AR)-positive PCa cells
The results showed that circulating exosomes derived from PCa patients are enriched with ITGA2

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among elder men [1]. PCa is a multifactorial disease, androgen and its receptor (AR) represent the main driving force for PCa progression. Different mechanisms are suggested to understand this phenomenon include AR gene mutation, AR splice variant expression, AR overexpression, transcription factors overexpression, and upregulation of the androgen synthesis enzymes [6,7,8,9,10,11]. These phenotype changes warranted further studies to understand the molecular mechanisms underlying PCa progression and metastasis [12]. Undeniable, a reasonable number of men diagnosed every year with PCa will experience progression from localized to advanced metastatic state [13]

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