Transforming growth factor-β signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation

被引：49

作者：

Futakuchi, Mitsuru ^{[1
,2
]}

Nannuru, Kalyan C. ^{[1
]}

Varney, Michelle L. ^{[1
]}

Sadanandam, Anguraj ^{[1
]}

Nakao, Kimihisa ^{[3
]}

Asai, Kiyofumi ^{[3
]}

Shirai, Tomoyuki ^{[4
]}

Sato, Shin-ya ^{[4
]}

Singh, Rakesh K. ^{[1
]}

机构：

[1] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA

[2] Nagoya City Univ, Grad Sch Med Sci, Dept Mol Toxicol, Nagoya, Aichi 4678601, Japan

[3] Nagoya City Univ, Grad Sch Med Sci, Dept Mol Neurobiol, Nagoya, Aichi 4678601, Japan

[4] Nagoya City Univ, Grad Sch Med Sci, Dept Expt Pathol & Tumor Biol, Nagoya, Aichi 4678601, Japan

来源：

CANCER SCIENCE | 2009年 / 100卷 / 01期

关键词：

BREAST-CANCER METASTASIS; HORMONE-RELATED PROTEIN; HUMAN PROSTATE-CANCER; TGF-BETA; EXPRESSION; CELLS; MODEL; MECHANISMS; MATRIX; DIFFERENTIATION;

D O I：

10.1111/j.1349-7006.2008.01012.x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor-bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-beta receptor 1 (TGF-beta RI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-beta RI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-beta activity by neutralizing antibody to TGF-beta or TGF-beta RI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-beta RI expression and its activation. In addition, we demonstrate a potential role of TGF-beta as an important modifier of receptor activator of NF-kappa B ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-beta RI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis. (Cancer Sci 2009; 100: 71-81).

引用

页码：71 / 81

页数：11

共 55 条

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