Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3K{gamma} to promote pancreatic cancer metastasis

Exosomes are emerging as important mediators of the crosstalk between tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer (PC) remain largely unknown. Here we found that hypoxic exosomes derived from PC cells activate macrophages to the M2 phenotype in a HIF-1a or HIF-2a-dependent manner, which then facilitates the migration, invasion, and EMT of PC 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 PC cells and enriched in hypoxic PC cells-derived exosomes. Circulating exosomal miR-301a-3p levels positively associated with depth of invasion, lymph node metastasis, late TNM stage, and poor prognosis of PC. Hypoxic exosomal miR-301a-3p induced the M2 polarization of macrophages via activation of the PTEN/PI3Kγ signaling pathway. Co-culturing of PC cells with macrophages in which miR-301a-3p was upregulated or treated with hypoxic exosomes enhanced their metastatic capacity. Collectively, these data indicate that PC cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of PC cells. Targeting exosomal miR-301a-3p may provide a potential diagnosis and treatment strategy for PC.

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