The Potential Role And Mechanism Of Tumor-Associated Macrophages-Derived Exosomes In The Metastasis And Chemoresistance Of Gastric Cancer

Objective: Tumor-associated macrophages(TAMs)can influence gastric cancer(GC)aggressiveness,but the detailed mechanisms remain unclear.As the important mediators in intercellular communications,exosomes secreted by host cells mediate the exchange of genetic material and protein to be involved in tumor aggressiveness.The aim of the present study was to investigate the role and mechanism of TAMs derived exosomes on the metastasis and chemoresistance of gastric cancer.Methods: The frequency and characterization of TAMs was analyzed in GC cohort using flow cytometry,immunohistochemistry,and real-time PCR.M2 polarized macrophages were obtained from mouse bone marrow or human PBMCs,and the function of polarized M2 macrophage was evaluated in vitro and in vivo.M2 macrophages-derived exosomes were isolated and the protein contents were identified by mass spectrometry.The functional researches of M2-exos on the metastasis of gastric cancer were further performed both in vivo and in vitro.Besides,miRNA expression profiles of M2-exos were analyzed using miRNA microarray.Then the role and mechanism of M2-exos on the chemoresistance of gastric cancer were further studied.Results: TAMs with an M2-polarized phenotype were increased in human gastric cancer tissues and correlated with the metastatic status.M2 macrophages promoted metastasis and chemoresistance of gastric cancer in vitro and in vivo mediated by exosomes.Mechanistically,exosomal transfer of ApoE by M2 macrophages activated PI3 K signaling on gastric cancer cells,which in turn upregulated AKT-mTOR signaling to remodel the cytoskeleton.Clinically,elevated ApoE is associated with metastasis and poor prognosis in human gastric cancer.Besides,further studies revealed that exosomal miR-21 can be directly transferred from macrophages to the gastric cancer cells,where it suppresses cell apoptosis and enhances chemoresistance to cisplatin by regulation of PTEN and BCL-2.Conclusions: In summary,our findings signify that the exosome-mediated transfer of functional proteins and miRNAs from M2-TAMs to the surrounding tumor cells promotes gastric cancer metastasis and chemoresistance,and targeting TAMs or exosome communication may be a promising new therapeutic strategy for gastric cancer patients.