Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-β type I receptor kinase in vivo
Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-β type I receptor kinase in vivo
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DOI：
10.1158/1078-0432.ccr-06-0162
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发表时间：
2006-07-15
影响因子：
11.5
通讯作者：
Reiss, Michael
中科院分区：
文献类型：
--
作者：
Ge, Rongrong;Rajeev, Vaishali;Reiss, Michael
目的：转化生长因子-β (TGF-β) 通过抑制细胞增殖、诱导分化和凋亡以及维持基因组完整性来抑制肿瘤发展。然而，一旦肿瘤细胞逃脱TGF-β的肿瘤抑制作用，它们通常会组成性过度表达并激活TGF-β，这可能通过增强侵袭、转移和血管生成以及抑制抗肿瘤免疫来促进肿瘤进展。本研究的目的是使用 TGF-β 途径拮抗剂来检验这一假设。 实验设计：我们在体外和体内检查了选择性 TGF-β I 型受体激酶抑制剂 SD-093 和 SD-208 对两种小鼠乳腺癌细胞系（R3T 和 4T1）的影响。结果：两种药物均阻断 TGF-β 诱导的 受体相关的 Smad、Smad2 和 Smad3 的磷酸化呈剂量依赖性，IC50 在 20 至 80 nmol/L 之间。 TGF-β 未能抑制这些细胞系的生长，但在体外刺激上皮间质转分化、迁移和侵入基质胶。这些效应被 SD-093 抑制，表明这些过程部分是由 TGF-β 驱动的。口服 SD-208 治疗同基因 R3T 或 4T1 荷瘤小鼠可抑制原发肿瘤生长以及转移瘤的数量和大小。相比之下，SD-208未能抑制无胸腺裸鼠中的R3T肿瘤生长或转移。此外，与对照动物的细胞相比，药物治疗动物的脾细胞的体外抗4T1细胞毒性T细胞反应增强。此外，SD-208治疗导致肿瘤血管生成减少。结论：TGF-βI型受体激酶抑制剂有望成为转移性乳腺癌的新型治疗药物。
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.