PGRN^-/- TAMs-derived exosomes inhibit breast cancer cell invasion and migration and its mechanism exploration

Breast cancer is one of the most malignant diseases world-wide and ranks the first among female cancers. Progranulin (PGRN) plays a carcinogenic role in breast cancer, but its mechanisms are not clear. In addition, there are few reports on the relationship between PGRN and tumor-associated macrophages (TAMs).

Aims: To investigate the effects of exosomes derived from PGRN^-/- TAMs on invasion and migration of breast cancer cells.

Main methods: Mouse breast cancer xenograft model was constructed to explore the effect of PGRN^-/- tumor environment (TME) on breast cancer. Flow cytometry was used to compare TAMs of wild type (WT) and PGRN^-/- tumor tissue. Transwell assay, wound healing assay and western blot were used to explore the effect of WT and PGRN^-/- TAMs and their exosomes on invasion, migration and epithelial-mesenchymal transition (EMT) of breast cancer cells. MicroRNA (miRNA) assay was used to find out the differentially expressed miRNA of negative control (NC) and siPGRN-TAMs exosomes. Quantitative PCR and luciferase report assay were used to explore the target gene.

Key findings: The lung metastasis of breast cancer of PGRN^-/- mice was inhibited. PGRN^-/- TAMs inhibited invasion, migration and EMT of breast cancer cells through their exosomes. MiR-5100 of PGRN^-/- TAMs-derived exosomes was up-regulated, which might regulate expression of CXCL12, thereby inhibiting the CXCL12/CXCR4 axis, and ultimately inhibiting the invasion, migration and EMT of breast cancer cells.

Significance: Our study elucidates a new molecular mechanism of lung metastasis of breast cancer, so it may contribute to efficient prevention and therapeutic strategies.