Extracellular vesicles transport variable content and have crucial functions in cell–cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers.

Metastases are the leading cause of cancer-related deaths, and their origin is not fully elucidated. Recently, studies have shown that extracellular vesicles (EVs), particularly small extracellular vesicles (sEV), can disrupt the homeostasis of organs, promoting the development of a secondary tumor. However, the role of sEV in brain endothelium and their association with metastasis related to breast cancer is unknown. Thus, this study aimed to investigate sEV-triggered changes in the phosphorylation state of proteins on the surface of brain endothelial cells, as they form the first barrier in contact with circulating tumor cells and EVs, and once identified, to modulate its interactors and effects from this through different functional assays. We used the most aggressive breast cancer cell line, MDA-MB-231, and its brain-seeking variant, MDA-MB-231-br. From these cells, small and large extracellular vesicles were harvested to treat hCMEC/D3 cells, an immortalized cell line from the human brain microvasculature. Higher levels of phosphorylation of VEGFR1 and VEGFR2 were found in hCMEC/D3 cells treated with MDA-MB-231-br sEV. By computational analysis, the Valosin-Containing Protein (VCP) was predicted to be an important sEV cargo affecting the VEGFR2 intracellular trafficking, validated by western blotting analysis. Then, VCP was modulated by cell transfection or chemical inhibition in hCMEC/D3 cells and assessed in different functional in vitro assays evidencing a significant effect on the functionality of these cells. Thus, this study demonstrates that the VCP-containing sEVs induce modifications at different phosphor sites of VEGFR2 and effectively modulate the state of brain microvascular endothelial cells.

Bone is the most common site of metastasis in breast cancer. Metastasis is promoted by acidosis, which is associated with osteoporosis. To investigate how acidosis could promote bone metastasis, we compared differentially expressed genes (DEGs) in MDA-MB-231 cancer cells in acidosis, bone metastasis, and bone metastatic tumors. The DEGs were identified using Biojupies and GEO2R. The expression profiles were assessed with Morpheus. The overlapping DEGs between acidosis and bone metastasis were compared to the bulk of the DEGs in terms of the most important genes and enriched terms using CytoHubba and STRING. The expression of the genes in this overlap filtered by secreted proteins was assessed in the osteoporosis secretome. The analysis revealed that acidosis-associated transcriptomic changes were more similar to bone metastasis than bone metastatic tumors. Extracellular matrix (ECM) organization would be the main biological process shared between acidosis and bone metastasis. The secretome genes upregulated in acidosis, bone metastasis, and osteoporosis-associated mesenchymal stem cells are enriched for ECM organization and angiogenesis. Therefore, acidosis may be more important in the metastatic niche than in the primary tumor. Acidosis may contribute to bone metastasis by promoting ECM organization. Untreated osteoporosis could favor bone metastasis through the increased secretion of ECM organization proteins.