Cancer-associated Fibroblasts Communicate with Breast Tumor Cells Through Extracellular Vesicles in Tumor Development

Abstract

Breast cancer is the leading cause of cancer death among women worldwide. In solid tumors, the microenvironment plays a critical role in tumor development, and it has been described a communication between the different cell types that conform the stroma, including fibroblasts, pericytes, adipocytes, immune cells and cancer-associated fibroblasts. Intercellular communication is bidirectional, complex, multifactorial and is mediated by the secretion of molecules and extracellular vesicles. The extracellular vesicles are vesicles limited by two membranes that are secreted by normal and cancer cells into the extracellular space. Extracellular vesicle cargo is complex and includes proteins, miRNAs, DNA and lipids, and their composition is specific to their parent cells. Extracellular vesicles are taken up for neighboring or distant cells. Particularly, extracellular vesicles from breast cancer cells are taken up for fibroblasts and it induces the activation of fibroblasts into cancer-associated fibroblasts. Interestingly, cancer associated fibroblasts release extracellular vesicles that are taken up for breast cancer cells and promote migration, invasion, proliferation, epithelial-mesenchymal transition, changes in metabolism, chemoresistance, evasion of immune system and remodeling of extracellular matrix. In addition, the enrichment of specific cargos in extracellular vesicles of breast cancer patients has been suggested to be used as biomarkers of the disease. Here we review the current literature about the intercommunication between tumor cells and cancer associated fibroblasts through extracellular vesicles in breast cancer.

Keywords: breast cancer; cancer-associated fibroblasts; extracellular vesicles; microenvironment; stroma.

Figure 1.

Biogenesis of EVs. Microvesicles bud directly from plasma membrane, whereas exosomes arise from multivesicular bodies. EVs interact with target cells through three mechanism: (1) EVs fusion with transfer of their cargos; (2) EVs endocytosis and release of their cargos; (3) Receptor ligand interaction with activation of signal transduction pathways. Figure created with BioRender.com (2022).

Figure 2.

Intercommunication between CAFs and breast cancer cells. Activation of breast cancer cells induces the release of EVs that activate normal fibroblasts into CAFs. Reprinted from “Tumor microenvironment with Callout,” by BioRender.com (2022).

Figure 3.

EVs from breast cancer cells induce the acquisition of CAF phenotype. Breast cancer cells release EVs carrying miRNAs, lipids, and proteins that activate normal fibroblasts into CAFs. The CAFs are functional and express proteins that act as factors to promote tumor development. Figure created with BioRender.com (2022).

Figure 4.

CAFs transfer their cargos to breast cancer cells through EVs supporting tumor growth and the acquisition of an aggressive phenotype. Tumor development is regulated by EVs through the induction of invasion, proliferation, migration and EMT. CAFs release EVs that mediate changes in metabolism, immune modulation and chemoresistance in breast cancer cells, and modulate the expression of ECM components. Figure created with BioRender.com (2022).