title: Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development.
abstract: Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNFα promoted the ability of macrophages to mediate this step. M2 macrophages were particularly potent when induced by IL4, IL10, and TGFβ. In contrast, IFNγ-lipopolysaccharide-induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden. Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Ziquan
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neurosciences, Centre for Molecular Medicine, Karolinska Hospital at Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden. Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P.R. China. yihai.cao@ki.se sunyuping@live.cn.
authors.forename: Meili
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden. Department of Clinical Pathology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hartman
authors.affiliation: Applied Immunology and Immunotherapy, Department of Clinical Neurosciences, Centre for Molecular Medicine, Karolinska Hospital at Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P.R. China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden. Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden. Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. yihai.cao@ki.se sunyuping@live.cn.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D063646:Carcinogenesis / Q000473:pathology*; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015027:Zebrafish
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha