Inhibition of TGFBIp expression reduces lymphangiogenesis and tumor metastasis

被引:21
作者
Maeng, Y-S [1 ]
Aguilar, B. [2 ]
Choi, S-I [1 ]
Kim, E. K. [1 ,3 ]
机构
[1] Yonsei Univ, Coll Med, Dept Ophthalmol, Corneal Dystrophy Res Inst, Seoul 120752, South Korea
[2] Univ Calif San Diego, Sect Cell & Dev Biol, La Jolla, CA 92093 USA
[3] Yonsei Univ, Coll Med, Brain Korea Plus Project Med Sci 21, Severance Biomed Sci Inst, Seoul, South Korea
基金
新加坡国家研究基金会;
关键词
CELL-ADHESION; VEGF-C; VASCULAR-PERMEABILITY; MOLECULAR-MECHANISMS; ENDOTHELIAL-CELLS; BREAST-CANCER; BETA-IG-H3; BETA; PROTEIN; GROWTH;
D O I
10.1038/onc.2015.73
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
Transforming growth factor-beta-induced protein (TGFBIp) is an extracellular matrix protein that has a role in a wide range of pathological conditions. However, the role of TGFBIp signaling in lymphangiogenesis is poorly understood. The purpose of this study was therefore to analyze the effects of TGFBIp on lymphangiogenesis and determine whether TGFBIp-related lymphangiogenesis is important for the metastasis of tumor cells. TGFBIp increased adhesion, migration, and morphologic differentiation of human lymphatic endothelial cells (LECs), consistent with an increase in lymphatic vessel sprouting in a three-dimensional lymphatic ring assay. TGFBIp also induced phosphorylation of intracellular signaling molecules SRC, FAK, AKT, JNK and ERK. TGFBIp-induced lymphatic vessel sprouting was inhibited by addition of anti-integrin beta 3 antibody and pharmacologic inhibitors of FAK, AKT, JNK or ERK. TGFBIp increased both CCL21 expression in LECs, a chemokine that actively recruits tumor cells expressing the cognate chemokine receptors to lymphatic vessels and LEC permeability by inducing the dissociation of VE-cadherin junctions between LECs via the activation of SRC signaling. In vivo, inhibition of TGFBIp expression in SW620 cancer cells dramatically reduced tumor lymphangiogenesis and metastasis. Collectively, our findings demonstrate that TGFBIp is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis.
引用
收藏
页码:196 / 205
页数:10
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