Hhip regulates tumor-stroma-mediated upregulation of tumor angiogenesis

被引:26
作者
Agrawal, Vijayendra [1 ,2 ]
Kim, Dong Young [1 ]
Kwon, Young-Guen [1 ]
机构
[1] Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul 120749, South Korea
[2] Sanford Burnham Med Res Inst Lake Nona, 6400 Sanger Rd, Orlando, FL 32827 USA
基金
新加坡国家研究基金会;
关键词
HEDGEHOG-INTERACTING PROTEIN; SIGNALING PATHWAY; SONIC HEDGEHOG; HEPATOCELLULAR-CARCINOMA; BINDING PROTEIN; BREAST-CANCER; CYCLIN D2; CELLS; MICROENVIRONMENT; PROGRESSION;
D O I
10.1038/emm.2016.139
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/- mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/-mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density.
引用
收藏
页码:e289 / e289
页数:8
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