Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks.
Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks.
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发表时间：
2005
期刊：
影响因子：
8
通讯作者：
N. Cheng;N. Bhowmick;A. Chytil;Agnieszka E Gorksa;K. Brown;R. Muraoka;C. Arteaga;E. Neilson;
中科院分区：
文献类型：
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作者：
N. Cheng;N. Bhowmick;A. Chytil;Agnieszka E Gorksa;K. Brown;R. Muraoka;C. Arteaga;E. Neilson;
间质成纤维细胞通过直接和间接的细胞-细胞相互作用调节上皮细胞的行为。为了阐明转化生长因子-β信号在间质成纤维细胞中的作用，我们有条件地敲除了小鼠乳腺成纤维细胞中的转化生长因子-β2型受体基因(TGFBR2(FspKO))。TGFBR2(FspKO)小鼠表现出乳腺导管发育缺陷，部分特征是导管上皮细胞周转增加与间质成纤维细胞丰度增加相关。TGFBR2(FspKO)与乳腺癌细胞共移植促进乳腺成纤维细胞的生长和侵袭，这与ErbB1、erbB2、RON和c-Met受体的活化磷酸化增加有关。此外，受体磷酸化的增加与TGFBR2(FspKO)成纤维细胞分泌同源配体的增加有关。用成纤维细胞条件培养液处理肿瘤细胞可增加肿瘤细胞的增殖和运动能力，这一作用可通过添加转化生长因子-α信号转导的药物抑制剂或巨噬细胞刺激蛋白(MSP)、HGF或c-Met的中和抗体来阻断。这些研究表明，间质转化生长因子-β信号通过调节转化生长因子-α、MSP和肝细胞生长因子信号通路，在乳腺组织动态平衡和乳腺肿瘤进展中发挥重要作用。
Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary fibroblasts (Tgfbr2(fspKO)). Tgfbr2(fspKO) mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2(fspKO) mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2(fspKO) fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-alpha signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-beta signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-alpha, MSP, and HGF signaling pathways.