Exosomes are emerging as important mediators of the cross-talk between
tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate
tumor development under
hypoxia in
pancreatic cancer remain largely unknown. Here, we found that hypoxic exosomes derived from
pancreatic cancer cells activate macrophages to the M2 phenotype in a HIF1a or HIF2a-dependent manner, which then facilitates the migration, invasion, and epithelial-mesenchymal transition of
pancreatic cancer cells. Given that exosomes have been shown to transport
miRNAs to alter cellular functions, we discovered that miR-301a-3p was highly expressed in hypoxic
pancreatic cancer cells and enriched in hypoxic
pancreatic cancer cell-derived exosomes. Circulating exosomal miR-301a-3p levels positively associated with depth of invasion,
lymph node metastasis, late TNM stage, and poor prognosis of
pancreatic cancer. Hypoxic exosomal miR-301a-3p induced the M2 polarization of macrophages via activation of the PTEN/PI3Kγ signaling pathway. Coculturing of
pancreatic cancer cells with macrophages in which miR-301a-3p was upregulated or treated with hypoxic exosomes enhanced their metastatic capacity. Collectively, these data indicate that
pancreatic cancer cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of
pancreatic cancer cells. Targeting exosomal miR-301a-3p may provide a potential diagnosis and treatment strategy for
pancreatic cancer.Significance: These findings identify an exosomal
miRNA critical for microenvironmental cross-talk that may prove to be a potential target for diagnosis and treatment of
pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4586/F1.large.jpg
Cancer Res; 78(16); 4586-98. ©2018 AACR.