title: IL33 Promotes Colon Cancer Cell Stemness via JNK Activation and Macrophage Recruitment.
abstract: The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growthin vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genesNANOG, NOTCH3, andOCT3/4via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer.Cancer Res; 77(10); 2735-45. ©2017 AACR.
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Qi
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Second Department of General Surgery, Medical University in Lublin, Lublin, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Zgodzinski
authors.affiliation: The Second Department of General Surgery, Medical University in Lublin, Lublin, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Majewski
authors.affiliation: The Second Department of General Surgery, Medical University in Lublin, Lublin, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wallner
authors.affiliation: Holycross Cancer Center, Kielce, Poland.
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Gozdz
authors.affiliation: Holycross Cancer Center, Kielce, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Macek
authors.affiliation: Holycross Cancer Center, Kielce, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Kowalik
authors.affiliation: Holycross Cancer Center, Kielce, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Pasiarski
authors.affiliation: Department of Clinical Immunology and Immunotherapy, Medical University in Lublin, Lublin, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Grywalska
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Linda
authors.initials: L
authors.lastname: Vatan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Nisha
authors.initials: N
authors.lastname: Nagarsheth
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.|Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.
authors.forename: Guobin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.|Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. lin_wang@hust.edu.cn wzou@med.umich.edu zhengwang@hust.edu.cn wgb@hust.edu.cn.|Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000378:metabolism; D000067596:Interleukin-33 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011379:Prognosis; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases