Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-β type I receptor kinase in vivo

被引:132
|
作者
Ge, Rongrong
Rajeev, Vaishali
Ray, Partha
Lattime, Edmund
Rittling, Susan
Medicherla, Satya
Protter, Andy
Murphy, Alison
Chakravarty, Jit
Dugar, Sundeep
Schreiner, George
Barnard, Nicola
Reiss, Michael
机构
[1] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Internal Med,Div Med Oncol, New Brunswick, NJ 08903 USA
[2] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol, New Brunswick, NJ 08903 USA
[3] Rutgers State Univ, Dept Genet, Piscataway, NJ USA
[4] Scios Inc, Fremont, CA USA
关键词
D O I
10.1158/1078-0432.CCR-06-0162
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Transforming growth factor-beta (TGF-beta) suppresses tumor development by inhibiting cellular proliferation, inducing differentiation and apoptosis, and maintaining genomic integrity. However, once tumor cells escape from the tumor-suppressive effects of TGF-beta, they often constitutively overexpress and activate TGF-beta, which may promote tumor progression by enhancing invasion, metastasis, and angiogenesis and by suppressing antitumor immunity. The purpose of this study was to test this hypothesis using TGF-beta pathway antagonists. Experimental Design: We examined the effects of selective TGF-beta type I receptor kinase inhibitors, SD-093 and SD-208, on two murine mammary carcinoma cell lines (R3T and 4T1) in vitro and in vivo. Results: Both agents blocked TGF-beta-induced phosphorylation of the receptor-associated Smads, Smad2 and Smad3, in a dose-dependent manner, with IC50 between 20 and 80 nmol/L. TGF-beta failed to inhibit growth of these cell lines but stimulated epithelial-to-mesenchymal transdifferentiation, migration, and invasiveness into Matrigel in vitro. These effects were inhibited by SD-093, indicating that these processes are partly driven by TGF-beta. Treatment of syngeneic R3T or 4T1 tumor-bearing mice with orally given SD-208 inhibited primary tumor growth as well as the number and size of metastases. In contrast, SD-208 failed to inhibit R3T tumor growth or metastasis in athymic nude mice. Moreover, in vitro anti-4T1 cell cytotoxic T-cell responses of splenocytes from drug-treated animals were enhanced compared with cells from control animals. In addition, SD-208 treatment resulted in a decrease in tumor angiogenesis. Conclusion: TGF-beta type I receptor kinase inhibitors hold promise as novel therapeutic agents for metastatic breast cancer.
引用
收藏
页码:4315 / 4330
页数:16
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