title: Tumor associated macrophages provide the survival resistance of tumor cells to hypoxic microenvironmental condition through IL-6 receptor-mediated signals.
abstract: Hypoxia and infiltration of tumor-associated macrophages (TAM) are intrinsic features of the tumor microenvironment. Tumor cells that remain viable in hypoxic conditions often possess an increased survival potential and tend to grow aggressively. TAM also respond to a variety of signals in the hypoxic tumor microenvironment and express a more M2-like phenotype. In this study, the established mouse tumor tissues showed a dense infiltration of CD206+macrophages at the junctions between the normoxic and hypoxic regions and an increased IL-6 receptor (IL-6R) expression of tumor cells in the areas of CD206+TAM accumulation, which indicates a role of M2 phenotype TAM in survival adaptation of tumor cells preparing for an impending hypoxic injury before changes in oxygen availability. Cocultured mouse FM3A or human MCF-7 tumor cells with tumor infiltrating macrophages isolated from mouse tumor tissues and M2-polarized macrophages generated from human THP-1 cells, respectively, showed significantly decreased rate of cell death in cultures exposed to hypoxia. The acquisition of survival resistance was attributed to increased IL-6 production by M2 TAM and increased expression of IL-6R in tumor cells in the coculture system. MCF-7 cells cocultured with M2 TAM showed activated JAK1/STAT3 and Raf/MEK/JNK pathways contributing to tyrosine and serine phophorylation of STAT3, respectively. However, only tyrosine phosphorylated STAT3 was detected in the nucleus, which induced upregulation of Bcl-2 and downregulation of Bax and Bak. Finally, knockdown of IL-6R by small interfering RNA significantly counteracted coculture-induced signals and completely abolished the survival resistance to hypoxic injury. Thus, we present evidence for the role of M2 phenotype TAM in IL-6 receptor-mediated signals, particularly tyrosine phosphorylation of STAT3, responsible for the prosurvival adaptation of tumor cells to hypoxia.
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea; Department of Microbiology, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Jeong
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: Joong Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: Chang Geun
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: You-Soo
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea.
authors.forename: Sung Dae
authors.initials: SD
authors.lastname: Kim
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Sun Ok
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Department of Microbiology, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Han
authors.affiliation: Department of Microbiology, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea.
authors.forename: Kyu Yeol
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Dong-A University College of Medicine, Daeshingongwon-gil 32, Seo-gu, Busan 602-714, Republic of Korea. Electronic address: mhjeong@dau.ac.kr.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences, Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan 619-953, Republic of Korea. Electronic address: sailorjo@dirams.re.kr.
authors.forename: Wol Soon
authors.initials: WS
authors.lastname: Jo
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D061986:MCF-7 Cells; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D016207:Cytokines; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor
keywords: Hypoxia; IL-6R; STAT3; Tumor microenvironment; Tumor-associated macrophages