title: Cancer Cell-derived Exosomes Induce Mitogen-activated Protein Kinase-dependent Monocyte Survival by Transport of Functional Receptor Tyrosine Kinases.
abstract: Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signal-regulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Song
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Ding
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China, the College of Pharmaceutical Science, Jilin University, Changchun 130021, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zhao
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China, the College of Pharmaceutical Science, Jilin University, Changchun 130021, China.
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China, the Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China, and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhao
authors.affiliation: the Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.affiliation: From the CAS Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety & CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, 11th Beiyitiao, Zhongguancun, Beijing 100190, China, niegj@nanoctr.cn.
authors.forename: Guangjun
authors.initials: G
authors.lastname: Nie
mesh_terms: D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D009000:Monocytes / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D020169:Caspases; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: caspase; exosome (vesicle); mitogen-activated protein kinase (MAPK); monocyte; receptor tyrosine kinase; survival; tumor microenvironment