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

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.

Tumor Microenvironment Heterogeneity: Challenges and Opportunities

“…Accumulating evidence support that CAFs facilitate tumor initiation, growth and progression (Calvo and Sahai, 2011; Castaño et al, 2012; Quail and Joyce, 2013) and tumor invasion and metastasis by mediating tumor-enhancing inflammation (Erez et al, 2010). The data suggests that CAFs strongly promote the development of an aggressive cancer cell phenotype (Donnarumma et al, 2017). It was found by differential expression profile analysis that three types of microRNAs (miRs -21, -378e, and -143) increased in exosomes from breast CAFs as compared from normal fibroblasts.…”

“…Accumulating evidence has supported that MSCs play critical roles in tumor development and progression, by increasing stemness of tumor cells, stimulating tumor cell migration, promoting angiogenesis, supporting immune responses, and inducing drug resistance. Additionally, MSCs increase the metastatic potential of tumor cells by advancing their motility and invasiveness and thereby play a role in the nature of a metastatic niche at the secondary site (Bott et al, 2017; Donnarumma et al, 2017; Gonzalez et al, 2017; Luo et al, 2009; McAndrews et al, 2015; Wolfe et al, 2016). Therefore, a comprehensive knowledge on the biology and mechanism of interaction between MSCs and TME of breast and prostate cancer is essential for the development of therapeutics that capitalize on vulnerabilities in these tumor cell-MSC interplay.…”

Cell‐to‐cell communication: microRNAs as hormones

“…(Donnarumma et al . (2017) showed that the release of specific miRNAs from CAF exosomes can promote oncogenic signaling in breast cancer. Their results demonstrated that three miRNAs (miR‐21, miR‐143, and miR‐378e) were significantly upregulated in CAF exosomes in respect to NF exosomes (Donnarumma et al ., 2017).…”

“…Their results demonstrated that three miRNAs (miR‐21, miR‐143, and miR‐378e) were significantly upregulated in CAF exosomes in respect to NF exosomes (Donnarumma et al ., 2017). When T47D luminal‐A breast cancer cells were treated with exosomes isolated from NFs and CAFs and labeled with PKH26, they found that T47D cells are able to take up exosomes derived from CAFs and NFs (Donnarumma et al ., 2017). Furthermore, they observed that CAF exosomes treatment significantly promoted stemness, EMT, invasiveness capacity, and anchorage‐independent cell growth (Donnarumma et al ., 2017).…”

Exosomes: The New Mediator of Peritoneal Membrane Function

“…miR-21, miR-378e and miR-143 were shown by Donnarumma and colleagues to exhibit a distinctly increased capacity for EMT. Decreasing exosomal delivery of miR-21, miR-378e and miR-143 can alleviate EMT [84]. Aside from the exosomal miRNAs mentioned above, other miRNAs derived from various cell types affect fibrosis (Table 1).…”