Exosomes: Small Vesicles with Important Roles in the Development, Metastasis and Treatment of Breast Cancer

Abstract

Breast cancer (BC) has now overtaken lung cancer as the most common cancer, while no biopredictive marker isolated from biological fluids has yet emerged clinically. After traditional chemotherapy, with the huge side effects brought by drugs, patients also suffer from the double affliction of drugs to the body while fighting cancer, and they often quickly develop drug resistance after the drug, leading to a poor prognosis. And the treatment of some breast cancer subtypes, such as triple negative breast cancer (TNBC), is even more difficult. Exosomes (Exos), which are naturally occurring extracellular vesicles (EVs) with nanoscale acellular structures ranging in diameter from 40 to 160 nm, can be isolated from various biological fluids and have been widely studied because they are derived from the cell membrane, have extremely small diameter, and are widely involved in various biological activities of the body. It can be used directly or modified to make derivatives or to make some analogs for the treatment of breast cancer. This review will focus on the involvement of exosomes in breast cancer initiation, progression, invasion as well as metastasis and the therapeutic role of exosomes in breast cancer.

Keywords: breast cancer; cancer therapeutics; drug resistance; exosome; targeted delivery.

Figure 1

(a) Exosomes are extracellular vesicles between 40 nm and 160 nm in diameter that begin with endocytosis and then mature and exhaled in the cell. (b) Its biomarkers include CD9, CD63, CD81, flotillin, ceramide, ARF6, TSG101 and Alix. (c) Its contents include various nucleic acids, proteins and lipids.

Figure 2

After activation of EZH2/STAT3 pathway, miR-378a-3p and miR-378d expression is increased in breast cancer cells treated with chemotherapy, which is released through exosome binding and endocytosis by surviving BC cells, resulting in chemoresistance.

Figure 3

The expression of α-lactalbumin was low in breast cancer cell line MDA- MB-231. After overexpression treatment, the exosomes released by it had the characteristics of α-lactalbumin overexpression. Through electroporation, ELANE and hiltonol are mixed into the interior, and the uptake of cancer cells induces ICD. Subsequently, various substances released activate cDC1s, causing the activation of CD8⁺T cells, and then killing cancer cells.

Figure 4

The exosomes were modified by FA and loaded with ultrasonic sensitizer ICG. After injection into the blood, they targeted the tumor tissue of mice and achieved local enrichment. Kill tumor tissue accurately.

Figure 5

Exosomes from tumors have related proteins that can mediate homologous targeting on the surface. After loading CuB and PTX-S-LA into the exosomes. The exosomes can achieve targeted capture of homologous proteins with CTCs after intravenous injection into the blood. After exosome uptake by CTCs, CuB targeted FAK/MMP pathway in CTCs is released to inhibit tumor metastasis, and ROS is also released, which promotes sequential activation of PTX-S-LA and releases PTX to inhibit tumor growth.

Figure 6

Mn²⁺ was used as an inducer to polarize macrophages into anti-tumor M1 macrophages. At the same time, the membrane is modified with azide groups through the inherent biosynthesis and metabolic incorporation of phospholipids. Then the azide modified M1 Exo was coupled with dibenzocyctocene (DBCO) modified anti-CD47 antibody (aCD47) and pH-sensitive anti-signal regulatory protein alpha (SIRPα) antibody (aSIRPα). After acid-induced division, antibodies are separated from exosomes, which repolarize M2-type macrophages into M1-type macrophages. ACD47 acts on CD47 overexpressed by tumor cells to resist the “don’t eat me” signal. Meanwhile, aSIRPa acts on SIRPA of macrophages to prevent phagocytic cells from losing their phagocytic ability. And then the phagocytes will eat the tumor cells.