Extracellular vesicles: the "Trojan Horse" within breast cancer host microenvironments

Abstract

Breast cancer represents a significant global health concern among women. The intricate processes and pathways underlying metastasis contribute to the challenging prognoses experienced by some patients. Extracellular vesicles (EVs) are membrane-bound structures characterized by phospholipid bilayers, capable of secretion by a multitude of cell types. The contents of these vesicles encompass a diverse assortment of lipids, proteins, nucleic acids, and cellular metabolites. The tumor microenvironment (TME) comprises a complex network involving tumor cells, non-cancerous cells, and an array of molecules they generate and release. Components include the extracellular matrix, cancer-associated fibroblasts, inflammatory immune cells, tumor-associated vasculature, and EVs discharged by these cellular entities. Within the TME, EVs serve as a mechanism akin to the "Trojan Horse," exerting significant influence in tumor initiation, progression, metastasis, and responses to therapeutic interventions. EVs originating from tumor cells and associated entities within the TME bolster processes such as stimulating angiogenesis adjacent to tumor sites, establishing pre-metastatic niches in distant anatomical regions, and inducing transformative changes in cancer cells to acquire characteristics promoting invasion, angiogenesis, immune evasion, distant metastasis, and resistance to chemotherapy. Noteworthy is the unique capacity of EVs to traverse biological barriers due to their inherent biocompatibility, rendering them promising candidates for innovative drug delivery systems. This attribute presents an avenue to surmount the constraints of traditional cancer treatments. This scholarly inquiry delves into the pathogenic mechanisms of EVs in breast cancer and delves into prospective therapeutic interventions, offering a groundwork for forthcoming precision-guided therapies tailored to breast cancer.

Keywords: Breast cancer; Drug delivery vehicles; Drug resistance; Extracellular vesicles; Metastasis; Pre-metastatic niche; Tumor microenvironment.

Fig. 1

BC cell-derived EVs, associated with the formation of a pre-metastatic niche via the transfer of miR-21, play an important role in promoting bone metastasis

Fig. 2

RalA and RalB decrease the amounts of adhesion molecules in exosomes to promote the metastatic ability of exosomes targeting the lung, whereas exosomes from RalA or RalB deficient cells have fewer organotypic abilities

Fig. 3

The interaction of exosomal CEMIP allowed the MDA-MB-231 BC cell line to develop the PMN

Fig. 4

In the microfluidic liver chip, BC-EVs activate LSECs, cause vascular barrier breakdown and epithelial-to-mesenchymal transition (EMT), and encourage cancer cell adhesion and invasion

Fig. 5

Role of exosomes in chemotherapy resistance in BC

Fig. 6

Exos-miR-182-5p, EVmiR-4488, Exos-circRNA-HIPK3 and EV-EPHA2 are absorpted by endothelial cells, and increase ECs proliferation, migration, and angiogenesis

Fig. 7

Monocytes were extracted from the bone marrow of mice with BC. Using GM-CSF and IL4 to convert the monocytes into immature dendritic cells (DCs) and collect and purify the EVs the DCs released. Let-7 and si-VEGF were electroporated into the cell and delivered specifically to the targeted BC cells after the cancer cell targeting ligand T-AS1411 had been loaded onto the cell’s surface. To prevent tumor development and angiogenesis, the tumor suppressor genes Let-7 and si-VEGF were expressed

Fig. 8

eNVs-FAP induced the number of FAP⁺CAFs in TME. It promoted the maturation of DCs. It also increased the infiltration of effector T cells into target tumor cells and FAP⁺ CAFs. The proportion of immunosuppressive cells in the TME, including M2-TAMs, MDSCs, and Regulatory cells (Tregs), was reduced. In vivo, experiments showed that in addition to down-regulating GPX4 by IFN-γ, eNVs-FAP could also promote ferroptosis by upregulating ALOX15. In addition, the combination of ferroptosis agonist RSL3 could synergistically enhance the ferroptosis of cancer cells to achieve the anti-tumor effect