Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis.
By Xiaofeng Wang, Guangtao Luo, Kun-dong Zhang, Jun Cao, Chen Huang, T. Jiang, Bing-ya Liu, Liping Su, Z. Qiu. Cancer Research, 2018
603 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/25f3f56dd35119b960d41190a4b16e8e9eea609c
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cancer Research
In Molecular Biology
Citations in the corpus
- Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer (2020, background): “The PTEN/AKT signaling pathway has been widely reported to be involved in macrophage polarization [20].”
- Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance (2019, background): “This transition promotes migration and EMT of pancreatic cancer cells which is due to activation of PTEN/PI3K pathway [87].”
- Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis (2019, background): “Additionally, Wang and colleagues revealed that pancreatic cancer (PC) cells activated macrophages to the M2 phenotype, which then promoted EMT progress to increase migration and invasion of PC cells [23].”
- Extracellular matrix (ECM) stiffness and degradation as cancer drivers (2018, background): “Alteration toward this protumor phenotype is under induction of hypoxia within the TME.(46,47) STAT3 released by cancer cells is also responsible for induction of M2 polarity.”