Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis
Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis
复制标题
DOI：
10.1158/0008-5472.can-06-3381
复制
发表时间：
2007-05-15
期刊：
影响因子：
11.2
通讯作者：
Mosesi, Harold L.
中科院分区：
文献类型：
--
作者：
Cheng, Nikki;Chytil, Anna;Mosesi, Harold L.
转化生长因子-β（TGF-β）作为肿瘤进展的抑制剂和促进剂发挥复杂的双重作用。虽然基质微环境对肿瘤进展的影响已被广泛认识，但对肿瘤进展期间基质中TGF-β信号传导的功能知之甚少。使用cre-lox技术，在成纤维细胞中选择性敲除H型TGF-β受体的表达（Tgfbr 2（FspKO））。在共异种移植模型中，我们显示Tgfbr 2（FspKO）成纤维细胞增强小鼠中乳腺癌生长和转移，同时增加肝细胞生长因子（HGF）表达和c-Met信号传导下游途径，包括信号转导和转录激活因子3（Stat 3）和p42/44丝裂原活化蛋白激酶（MAPK）。用c-Met的药理学抑制剂（EXEL-7592）治疗荷瘤小鼠可阻断肿瘤进展并降低磷酸化-Stat 3和磷酸化-p42/44 MAPK的水平。类似地，乳腺肿瘤细胞中c-Met表达的小干扰RNA敲低可减少Tgfbr 2（FspKO）成纤维细胞引起的转移和c-Met信号传导。结果显示成纤维细胞中的TGF-β信号传导通过拮抗肿瘤上皮细胞内的HGF/c-Met信号传导来抑制肿瘤转移。此外，这种共异种移植模型代表了研究乳腺肿瘤发生中基质TGF-β和HGF信号传导的独特背景。
Transforming growth factor-beta (TGF-beta) plays complex dual roles as an inhibitor and promoter of tumor progression. Although the influence of the stromal microenvironment on tumor progression is well recognized, little is known about the functions of TGF-beta signaling in the stroma during tumor progression. Using cre-lox technology, expression of the type H TGF-beta receptor was selectively knocked out in fibroblasts (Tgfbr2(FspKO)). in a co-xenograft model, we show that Tgfbr2(FspKO) fibroblasts enhance mammary carcinoma growth and metastasis in mice while increasing hepatocyte growth factor (HGF) expression and c-Met signaling downstream pathways including signal transducers and activators of transcription 3 (Stat3) and p42/44 mitogen-activated protein kinase (MAPK). Treatment of tumor-bearing mice with a pharmacologic inhibitor (EXEL-7592) of c-Met blocks tumor progression and reduces levels of phospho-Stat3 and phospho-p42/44 MAPK Similarly, small interfering RNA knockdown of c-Met expression in mammary tumor cells reduces metastasis and c-Met signaling caused by Tgfbr2(FspKO) fibroblasts. The results show that TGF-beta signaling in fibroblasts suppresses tumor metastasis by antagonizing HGF/c-Met signaling within tumor epithelial cells. Furthermore, this co-xenograft model represents a unique context to study stromal TGF-beta and HGF signaling in mammary tumorigenesis.