Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer.

Elvira Donnarumma,Salvatore Piscuoglio,Giuseppina Roscigno,Gerolama Condorelli,Martina Nappa,Valentina Russo,Assunta Adamo,Margherita Iaboni,Danilo Fiore,Cristina Quintavalle,Renato Thomas,Alessandra Affinito,Anna Rienzo,Ilaria Puoti

doi:10.18632/oncotarget.14752

Abstract

Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment. They may drive tumor progression, although the mechanisms involved are still poorly understood. Exosomes have emerged as important mediators of intercellular communication in cancer. They mediate horizontal transfer of microRNAs (miRs), mRNAs and proteins, thus affecting breast cancer progression. Differential expression profile analysis identified three miRs (miRs -21, -378e, and -143) increased in exosomes from CAFs as compared from normal fibroblasts. Immunofluorescence indicated that exosomes may be transferred from CAFs to breast cancer cells, releasing their cargo miRs. Breast cancer cells (BT549, MDA-MB-231, and T47D lines) exposed to CAF exosomes or transfected with those miRs exhibited a significant increased capacity to form mammospheres, increased stem cell and epithelial-mesenchymal transition (EMT) markers, and anchorage-independent cell growth. These effects were reverted by transfection with anti-miRs. Similarly to CAF exosomes, normal fibroblast exosomes transfected with miRs -21, -378e, and -143 promoted the stemness and EMT phenotype of breast cancer cells. Thus, we provided evidence for the first time of the role of CAF exosomes and their miRs in the induction of the stemness and EMT phenotype in different breast cancer cell lines. Indeed, CAFs strongly promote the development of an aggressive breast cancer cell phenotype.

Highlights

Breast cancer is the most common cancer in women, and is only second to lung cancer for cancerrelated mortality [1]
To identify oncogenic miRs in Cancer-associated fibroblasts (CAFs) exosomes, we conducted genome-wide expression profiling of miRs, comparing exosomal miRs derived from two breast CAF cultures and two normal fibroblast (NF) cultures
We found that three miRs were significantly up-regulated in CAF exosomes respect to NF exosomes: miR-21-5p, miR378e, and miR-143-3p (Table 1)

Summary

Introduction

Breast cancer is the most common cancer in women, and is only second to lung cancer for cancerrelated mortality [1]. Cancerassociated fibroblasts (CAFs), the major components of tumor stroma, are active fibroblasts that, to myofibroblasts, are highly heterogeneous, acquire contractile features, and express α-smooth-muscle actin (α-SMA) [2]. Active fibroblasts play similar roles in wound healing and in cancer, which may be considered as a wound that does not heal [3]. CAFs represent 80% of the resident fibroblasts in breast tumors. Accumulated evidence indicates that they play an important role in cancer initiation, angiogenesis, invasion, and metastasis of breast cancer [4,5,6]. CAFs represent an attractive target for cancer therapy

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Conclusion