Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer
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Elvira Donnarumma1, Danilo Fiore2, Martina Nappa2, Giuseppina Roscigno2, Assunta Adamo2, Margherita Iaboni2, Valentina Russo2, Alessandra Affinito2, Ilaria Puoti2, Cristina Quintavalle4, Anna Rienzo3, Salvatore Piscuoglio4, Renato Thomas5, Gerolama Condorelli2,3
1IRCCS-SDN, Naples, Italy
2Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of Naples, Naples, Italy
3IEOS, CNR, Naples, Italy
4University Hospital Basel, Basel, Switzerland
5Department of Surgical and Oncology, Clinica Mediterranea, Naples, Italy
Gerolama Condorelli, email: [email protected]
Keywords: exosomes, breast cancer, microenvironment, cancer-associated fibroblasts, microRNAs
Received: September 02, 2016 Accepted: December 27, 2016 Published: January 19, 2017
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.
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