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

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-beta 1 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-beta 1 and JNK pathways in this process. Moreover, the glioma-induced angiogenesis was associated with macrophage infiltration that was further enhanced by TGF-beta 1. 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. (C) 2012 Elsevier B.V. All rights reserved.