TGF-β1 enhances tumor-induced angiogenesis via JNK pathway and macrophage infiltration in an improved zebrafish embryo/xenograft glioma model

Int Immunopharmacol. 2013 Feb;15(2):191-8. doi: 10.1016/j.intimp.2012.12.002. Epub 2012 Dec 21.


Angiogenesis plays a crucial role at the early stage of tumorigenesis and tumor progression. A suitable model will be useful not only for the clarification of the underlying molecular mechanisms, but also for high-throughput identification of novel anti-angiogenesis compounds. Here, we established a zebrafish model for the purpose to investigate angiogenesis and screen anti-angiogenic compounds. Glioma U87 cells expressing red fluorescent protein (RFP) were transplanted in fli:GFP transgenic zebrafish embryos where significant angiogenesis was observed. TGF-β1 enhanced glioma-induced angiogenesis, which was inhibited by JNK inhibitor SP600125 but not p38 MAPK inhibitor SB202190, ERK inhibitor PD98059, or PI3K inhibitor LY294002, indicating the important role of TGF-β1 and JNK pathways in this process. Moreover, the glioma-induced angiogenesis was associated with macrophage infiltration that was further enhanced by TGF-β1. Therefore, our zebrafish model provides a powerful in vivo tool for the investigation of tumor-induced angiogenesis, and a cost-effective system for high-throughput screening of anti-angiogenic compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / isolation & purification*
  • Animals
  • Animals, Genetically Modified
  • Anthracenes / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chromones / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Flavonoids / pharmacology
  • Glioma / blood supply*
  • High-Throughput Screening Assays*
  • Humans
  • Imidazoles / pharmacology
  • MAP Kinase Kinase 4 / antagonists & inhibitors
  • Macrophages / drug effects
  • Morpholines / pharmacology
  • Neovascularization, Pathologic*
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines / pharmacology
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta1 / pharmacology*
  • Xenograft Model Antitumor Assays*
  • Zebrafish*


  • Angiogenesis Inhibitors
  • Anthracenes
  • Chromones
  • Flavonoids
  • Imidazoles
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Transforming Growth Factor beta1
  • pyrazolanthrone
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 4
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one