Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor.
Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor.
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DOI：
10.1210/en.2002-220007
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发表时间：
2002-09
期刊：
影响因子：
4.8
通讯作者：
Hong-zheng Zhang;J. Bennett;Kyle T. Smith;N. Sunil;S. Haslam
中科院分区：
文献类型：
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作者：
Hong-zheng Zhang;J. Bennett;Kyle T. Smith;N. Sunil;S. Haslam
上皮-基质细胞的相互作用对小鼠乳腺的正常发育和功能非常重要。类固醇激素雌激素是体内上皮细胞增殖和导管发育所必需的。最近对雌激素受体α基因敲除小鼠的研究表明，雌激素诱导的增殖依赖于乳腺基质细胞中雌激素受体的存在，而不是上皮细胞中雌激素受体的存在。本研究的目的是确定雌激素依赖的间质来源对乳腺上皮的潜在作用机制。我们开发了一种最低限度补充的无血清培养液，胶原凝胶原代乳腺共培养体系，以解决基质来源的、雌激素依赖的对上皮细胞增殖的影响。乳腺成纤维细胞的条件培养液或与乳腺成纤维细胞共培养可促进上皮细胞的增殖，并形成管状/导管形态。肝细胞生长因子(HGF)被认为是这一效应的中介，因为抗HGF的中和抗体可完全消除成纤维细胞条件培养液中的增殖活性，而抗表皮生长因子或IGF-I的中和抗体则不起作用。雌激素处理乳腺成纤维细胞可增加HGF的产生。这些结果表明，雌激素可能通过调节乳腺基质细胞中的HGF间接介导乳腺上皮细胞的增殖，HGF在体内雌激素诱导的乳腺上皮细胞增殖中起重要作用。
Epithelial-stromal cell interactions are important for normal development and function of the mouse mammary gland. The steroid hormone estrogen is required for epithelial cell proliferation and ductal development in vivo. Recent studies of estrogen receptor alpha knockout mice indicate that estrogen-induced proliferation is dependent upon the presence of estrogen receptor in mammary stromal cells, but not in epithelial cells. The purpose of the present study was to identify the underlying mechanism of estrogen-dependent stroma-derived effects on mammary epithelium. We have developed a minimally supplemented serum-free medium, collagen gel primary mammary coculture system to address the issue of stroma-derived, estrogen-dependent effects on epithelial cell proliferation. Conditioned medium from mammary fibroblasts or coculture with mammary fibroblasts caused increased epithelial cell proliferation and produced tubular/ductal morphology. Hepatocyte growth factor (HGF) was identified as the mediator of this effect, as the proliferative activity in fibroblast-conditioned medium was completely abolished by neutralizing antibody to HGF, whereas neutralizing antibodies to either epidermal growth factor or IGF-I had no effect. Treatment of mammary fibroblasts with estrogen increased the production of HGF. From these results we conclude that estrogen may indirectly mediate mammary epithelial cell proliferation via the regulation of HGF in mammary stromal cells and that HGF plays a crucial role in estrogen-induced proliferation in vivo.