title: Enhanced angiogenesis, hypoxia and neutrophil recruitment during Myc-induced liver tumorigenesis in zebrafish.
abstract: Angiogenesis, hypoxia and immune cells are important components in tumor microenvironment affecting tumor growth. Here we employed a zebrafish liver tumor model to investigate the effect of Myc expression on angiogenesis, hypoxia and tumor-infiltrated neutrophils during the tumor initiation stage. We found that induced Myc expression in the liver caused a dramatic increase of liver size with neoplastic features. The tumorigenic liver was accompanied by enhanced angiogenesis and inhibition of angiogenesis by an inhibitor (SU5416 or sunitinib) hindered the tumorigenic growth, suggesting an essential role of angiogenesis in tumorigenic growth of liver tumor in this zebrafish model. Myc induction also caused hypoxia, which could be further enhanced by hypoxia activator, ML228, to lead to a further enlargement of tumorigenic liver. Furthermore, Myc overexpression incurred an increase of liver-infiltrated neutrophils and the increase could be suppressed by angiogenesis inhibitors or by morpholino knockdown inhibition of neutrophil differentiation, leading to a suppression of growth of tumorigenic livers. Finally, the enhanced angiogenesis, hypoxia and tumor-infiltrated neutrophils by Myc overexpression were validated by RT-qPCR examination of expression of relevant biomarker genes. In sum, the current study demonstrated that the Myc-induced liver tumor model in zebrafish provides an excellent platform for study of tumor microenvironment.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Tony Weixi
authors.initials: TW
authors.lastname: Ding
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Gong
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000276:immunology; D020556:Neutrophil Infiltration; D009929:Organ Size; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment; D015027:Zebrafish
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc