Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis
Authors: Chen Huang
Bingya Liu
Kundong Zhang
Zhengjun Qiu
Guangtao Luo
Tao Jiang
Jun Cao
Xiaofeng Wang
Liping Su
Journal: Cancer research (2018)
Discipline: CLINICAL MEDICINE
Keywords: Exosomes; tumor development; hypoxia; pancreatic cancer; macrophages
Affiliations: Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (originally named "Shanghai First People's Hospital"), Shanghai, P.R. China., Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China., Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.  ., Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (originally named "Shanghai First People's Hospital"), Shanghai, P.R. China.  .

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.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. 

Retracted: No

PubPeer comments:
 2020 correction. https: cancerres.aacrjournals.org content 80 4 922 In the original version of this article (1), the image depicting the effect of macrophages treated with PANC-1-H-exo and transfected with PI3Ku03b3 siRNA on pancreatic cancer cells invasion in the bottom left panel of Fig. 5L is incorrect. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error. Reference 1.u21b5Wang X, Luo G, Zhang K, Cao J, Huang C, Jiang T, et al. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN PI3Ku03b3 to promote pancreatic cancer metastasis. Cancer Res 2018;78:4586u201398. ,