Abstract
BackgroundExosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs (miRNAs), participate in tumor pathogenesis and progression by modulating microenvironment. Our study aims to investigate the role of these microRNA-501-3p (miR-501-3p) containing exosomes derived from tumor-associated macrophage (TAM) in the progression of pancreatic ductal adenocarcinoma (PDAC).MethodsFirstly, the function of TAM recruitment in PDAC tissues was assessed, followed by identification of the effects of M2 macrophage-derived exosomes on PDAC cell activities and tumor formation and metastasis in mice. In silico analysis was conducted to predict differentially expressed genes and regulatory miRNAs related to PDAC treated with macrophages, which determined miR-501-3p and TGFBR3 for subsequent experiments. Next, gain- and loss-of-function experiments were performed to examine their role in PDAC progression with the involvement of the TGF-β signaling pathway.ResultsTAM recruitment in PDAC tissues was associated with metastasis. Highly expressed miR-501-3p was observed in PDAC tissues and TAM-derived exosomes. Both M2 macrophage-derived exosomes and miR-501-3p promoted PDAC cell migration and invasion, as well as tumor formation and metastasis in nude mice. MiR-501-3p was verified to target TGFBR3. PDAC cells presented with down-regulated TGFBR3, which was further decreased in response to M2 macrophage treatment. TGF-β signaling pathway activation was implicated in the promotion of miR-501-3p in PDAC development. The suppression of macrophage-derived exosomal miR-501-3p resulted in the inhibition of tumor formation and metastasis in vivo.ConclusionM2 macrophage-derived exosomal miR-501-3p inhibits tumor suppressor TGFBR3 gene and facilitates the development of PDAC by activating the TGF-β signaling pathway, which provides novel targets for the molecular treatment of PDAC.
Highlights
Exosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs, participate in tumor pathogenesis and progression by modulating microenvironment
M2 macrophage-derived exosomes promote the migration and invasion of pancreatic ductal adenocarcinoma (PDAC) cells It has been reported that macrophages can regulate the development of PDAC through miRNAs carried by exosomes [24]
A previous study provided an opposing view to the previous one suggesting that, when the PDAC cells were transfected with miR-encoding plasmid, the altered tumor-derived exosomes could control the polarization of macrophage phenotypes, making genetic therapies potential treatment options for pancreatic cancers [35]
Summary
Exosomes from cancer cells or immune cells, carrying bio-macromolecules or microRNAs (miRNAs), participate in tumor pathogenesis and progression by modulating microenvironment. Our study aims to investigate the role of these microRNA-501-3p (miR-501-3p) containing exosomes derived from tumor-associated macrophage (TAM) in the progression of pancreatic ductal adenocarcinoma (PDAC). Pancreatic cancer represents the seventh leading cause of death in relation to cancers, and the most common type is pancreatic ductal adenocarcinoma (PDAC), an infiltrating cancer with glandular differentiation originating from pancreatic ductal tree [1]. The recurrence of PDAC is a common occurrence following resection surgery, which exacerbates and usually results in the development of liver metastasis, lung metastasis, peritoneal seeding, peripancreatic recurrence, and other distant metastases [4, 5]. There is an urgent need to identify promising biomarkers that regulate biological activities of PDAC cells, in order to develop new therapeutic modalities for PDAC with favorable and accurate prognosis
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