期刊
ONCOGENE
卷 24, 期 32, 页码 5053-5068出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208685
关键词
TGF-beta; TGF-beta receptor type II; mammary gland; tumor-stromal interactions; tumor progression; subrenal grafting
资金
- NCI NIH HHS [R01 CA108646, CA85492, T32 CA009592, R01 CA085492, P30 CA068485, R01 CA108646-01, R01 CA102162, CA102162, P30 CA68485] Funding Source: Medline
- NIAMS NIH HHS [P30 AR041943, AR41943] Funding Source: Medline
Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal. broblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary. broblasts (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. broblasts 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). broblasts. 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.
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