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

胰腺癌 微泡 癌症研究 转移 外体 肿瘤微环境 PTEN公司 PI3K/AKT/mTOR通路 小RNA 生物 医学 癌症 巨噬细胞极化 癌细胞 信号转导 内科学 细胞生物学 巨噬细胞 体外 肿瘤细胞 基因 生物化学
作者
Xiaofeng Wang,Guangtao Luo,Kundong Zhang,Jun Cao,Chen Huang,Tao Jiang,Bingya Liu,Liping Su,Zhengjun Qiu
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:78 (16): 4586-4598 被引量:517
标识
DOI:10.1158/0008-5472.can-17-3841
摘要

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.
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