Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation
Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation
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DOI：
10.1074/jbc.m611739200
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发表时间：
2007-05-18
影响因子：
4.8
通讯作者：
Friedl, Andreas
中科院分区：
文献类型：
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作者：
Su, Gui;Blaine, Stacy A.;Friedl, Andreas
细胞表面硫酸肝素蛋白聚糖syndecan-1在乳腺癌间质成纤维细胞中被诱导并参与一个互反回路，刺激癌细胞在体内和体外的生长。为了明确肿瘤生长刺激的分子机制，我们建立了一个三维共培养模型，将T47D乳腺癌细胞与永生化人乳腺成纤维细胞结合在胶原凝胶中。通过短干扰RNA沉默内源性syndecan-1诱导并表达突变小鼠syndecan-1构建物，我们确定癌细胞有丝分裂需要syndecan-1从成纤维细胞表面蛋白水解脱落。旁分泌生长信号是由syndecan-1硫酸肝素链介导的，而不是核心蛋白的外域和所需的成纤维细胞生长因子2和基质源性因子1。这种旁分泌途径可能为间质上皮信号的治疗中断提供了机会。
The cell surface heparan sulfate proteoglycan syndecan-1 is induced in stromal fibroblasts of breast carcinomas and participates in a reciprocal feedback loop, which stimulates carcinoma cell growth in vitro and in vivo. To define the molecular mechanism of carcinoma growth stimulation, a three-dimensional co-culture model was developed that combines T47D breast carcinoma cells with immortalized human mammary fibroblasts in collagen gels. By silencing endogenous syndecan-1 induction with short interfering RNA and expressing mutant murine syndecan-1 constructs, it was determined that carcinoma cell mitogenesis required proteolytic shedding of syndecan-1 from the fibroblast surface. The paracrine growth signal was mediated by the syndecan-1 heparan sulfate chains rather than the ectodomain of the core protein and required fibroblast growth factor 2 and stroma-derived factor 1. This paracrine pathway may provide an opportunity for the therapeutic disruption of stroma-epithelial signaling.