EV-miRNA-Mediated Intercellular Communication in the Breast Tumor Microenvironment

Abstract

Cancer research has prioritized the study of the tumor microenvironment (TME) as a crucial area of investigation. Understanding the communication between tumor cells and the various cell types within the TME has become a focal point. Bidirectional communication processes between these cells support cellular transformation, as well as the survival, invasion, and metastatic dissemination of tumor cells. Extracellular vesicles are lipid bilayer structures secreted by cells that emerge as important mediators of this cell-to-cell communication. EVs transfer their molecular cargo, including proteins and nucleic acids, and particularly microRNAs, which play critical roles in intercellular communication. Tumor-derived EVs, for example, can promote angiogenesis and enhance endothelial permeability by delivering specific miRNAs. Moreover, adipocytes, a significant component of the breast stroma, exhibit high EV secretory activity, which can then modulate metabolic processes, promoting the growth, proliferation, and migration of tumor cells. Comprehensive studies investigating the involvement of EVs and their miRNA cargo in the TME, as well as their underlying mechanisms driving tumoral capacities, are necessary for a deeper understanding of these complex interactions. Such knowledge holds promise for the development of novel diagnostic and therapeutic strategies in cancer treatment.

Keywords: cancer progression; extracellular vesicles; metastasis; miRNAs; small EVs; tumor progression.

Figure 1

Delivery of EV-miRs secreted by tumor cells promotes vascular permeability and angiogenesis in BC. Tumor cells and other cells in the TME (A) secrete and deliver EV-miRs (B), the incorporation of which by endothelial recipient cells favors the disruption of endothelial integrity (C), vascular permeability, and angiogenesis, which can finally end in tumor nourishment, tumor cell intravasation, and dissemination. EV-miRs involved in the regulation of angiogenesis and permeability are listed in the figure and include EV-miR-182-5p, -210, -126, 92a, -9, -105, and 939, among others.

Figure 2

BC tumor-derived or/and CAF-derived EVs promote EMT in BC tumor recipient cells. (A) High heterogeneity in a primary BC tumor is important when considering cell–cell communication and crosstalk between different cell types and between tumor cells with different properties and transformations. BC-derived EV-miRs can promote EMT in less aggressive BC recipient cells in a paracrine manner. (B) Among the EV-miRs implicated in these changes are miR-378, miR-21, miR-143, and miR-18b. On the other hand, CAFs in the BC TME also secrete EVs and EV-miRs and have a role in the promotion of EMT. (C) EV-miR-10b, -miR-146a, and -miR-221, among others, are secreted by CAFs and can promote the acquisition of EMT in BC tumor cells.

Figure 3

Extracellular vesicles secreted by adipocytes and miRNA cargo. (A) The extracellular vesicles secreted by adipocytes (ADEVs) are represented in yellow, and the miRNAs described to date are shown in the yellow rectangle. (B) In the context of the tumor microenvironment, these adipocytes are transformed into cancer-associated adipocytes (CAAs), and the presence of miR-21 in EVs secreted by CAAs has been described.

Figure 4

Heterogeneity in primary breast cancer tumor and EV-miRNA-mediated cell–cell communication. The tumor microenvironment is heterogeneous due to the presence of different types of cells and secreted factors. Among the secreted factors, extracellular vesicles and their miRNA cargo contribute to cell–cell communication and cancer progression. (A) CAF-derived EV-miRs can promote EMT in BC. (B) BC-derived EV-miRNA facilitate endothelial permeability and promote angiogenesis within the BC microenvironment. (C) ADEV miRNAs can interact with BC tumor cells and promote BC progression. Adipocytes are transformed into CAAs and only the presence of miR-21 in secreted EVs has been described. To date, the effect of CAA EV-miRNAs and whether these EVs impact ECs remains unknown. The signal “?” represents cellular communication mediated by extracellular vesicles and miRNAs, which is unknown and requires further investigation. ADEVs: adipose-derived extracellular vesicles; BBB: blood–brain barrier; BC: breast cancer; CAAs: cancer-associated adipocytes; CAFs: cancer-associated fibroblasts; EC: endothelial cells; EMT: epithelial–mesenchymal transition; EVs: extracellular vesicles.