Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis

Abstract

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. 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. http://cancerres.aacrjournals.org/content/canres/78/16/4586/F1.large.jpg .

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival

“…Interestingly, a slight increase in size of SEV was observed under moderate hypoxia (1.0% O 2 ) in both the cell lines. 33 In other studies, EVs derived from a variety of cancer cells grown under hypoxia are shown to contain miR-21, 45,46 a downstream target of HIF-1α, which plays important roles in hypoxic tumor cell survival. However, an increased release of EV under hypoxia counters this argument.…”

“…18,33 Furthermore, it has also been demonstrated that their biogenesis and shedding can be influenced by extracellular stimuli, which holds broader functional significance. Although initially believed to serve as trash bags to get rid of unwanted cellular material, EVs are now established as functional entities that are capable of altering the properties of the recipient cells through transfer of bioactive cargo.…”

Exosomal miRNAs as potential biomarkers for acute myocardial infarction

“…The dysregulation of miRNA activity can lead to F I G U R E 4 Size of the exosomes in the serum of SCAD patients, confirmed using the NanoSight instrument. SCAD, stable coronary artery disease immune responses in severe asthma (fibroblast-derived exosomes promote epithelial cell proliferation through the TGF-beta2 signalling pathway), 22 pancreatic cancer metastasis (exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ), 23 non-small-cell lung cancer (exosomal miR-451a), 24 acute coronary syndrome (exosomal miR-208a), 25 and so on. Compared with plasma or serum miRNAs, exosomal miRNAs are accurate, sensitive, and specific.…”

The cancer exosomes: Clinical implications, applications and challenges

“…Exosome and its components coactivate intercellular cross‐talk between metastatic malignancy and normal tissue under environmental low oxygen tension. Wang et al . purposed that anoxic pancreatic tumor cells recruited exosomal miR‐301a‐3p to trigger the M2 polarization of macrophages through the PTEN/PI3Kγ axis, led to a greater invasive depth of cancer cells as well as EMT (Table ).…”

“…Exosome and its components coactivate intercellular cross-talk between metastatic malignancy and normal tissue under environmental low oxygen tension. Wang et al 31 purposed that anoxic pancreatic tumor cells recruited exosomal miR-301a-3p to trigger the M2 polarization of macrophages through the PTEN/PI3Kγ axis, led to a greater invasive depth of cancer cells as well as EMT (Table 1). And Xue et al 32 isolated and identified hypoxic bladder cancer cell-derived exosomes, and their result showed that oncogenic lncRNA-UCA1-enriched exosomes remodeled tumor microenvironment to facilitate tumor growth (Table 1).…”