Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis

被引：165

作者：

Korpal, Manav ^{[1
]}

Yan, Jun ^{[1
]}

Lu, Xin ^{[1
]}

Xu, Shuwa ^{[1
]}

Lerit, Dorothy A. ^{[1
]}

Kang, Yibin ^{[1
,2
]}

机构：

[1] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[2] Canc Inst New Jersey, Breast Canc Program, New Brunswick, NJ USA

来源：

NATURE MEDICINE | 2009年 / 15卷 / 08期

关键词：

RECEPTOR-TYPE-I; TGF-BETA; ORAL IBANDRONATE; TUMOR; DISEASE; CELLS; VIVO; INHIBITORS; MICE; BISPHOSPHONATES;

D O I：

10.1038/nm.1943

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：

Although the transforming growth factor-beta (TGF-beta) pathway has been implicated in breast cancer metastasis, its in vivo dynamics and temporal-spatial involvement in organ-specific metastasis have not been investigated. Here we engineered a xenograft model system with a conditional control of the TGF-beta-SMAD signaling pathway and a dual-luciferase reporter system for tracing both metastatic burden and TGF-beta signaling activity in vivo. Strong TGF-beta signaling in osteolytic bone lesions is suppressed directly by genetic and pharmacological disruption of the TGF-beta-SMAD pathway and indirectly by inhibition of osteoclast function with bisphosphonates. Notably, disruption of TGF-beta signaling early in metastasis can substantially reduce metastasis burden but becomes less effective when bone lesions are well established. Our in vivo system for real-time manipulation and detection of TGF-beta signaling provides a proof of principle for using similar strategies to analyze the in vivo dynamics of other metastasis-associated signaling pathways and will expedite the development and characterization of therapeutic agents.

引用

页码：960 / U169

页数：8

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