Fibroblast hepatocyte growth factor promotes invasion of human mammary ductal carcinoma in situ.
Fibroblast hepatocyte growth factor promotes invasion of human mammary ductal carcinoma in situ.
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DOI：
10.1158/0008-5472.can-09-1043
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Sloane BF
中科院分区：
文献类型：
--
作者：
Jedeszko C;Victor BC;Podgorski I;Sloane BF
间质源性肝细胞生长因子(HGF)通过其特异的原癌基因受体c-Met在调节肿瘤细胞迁移和侵袭中发挥旁分泌作用。浸润性导管原位癌(DCIS)向浸润性乳腺癌的转变主要表现为间质成纤维细胞的浸润和基底膜的缺失。我们假设浸润性成纤维细胞产生的HGF可能改变DCIS细胞的蛋白分解途径，为了研究这一假设，我们建立了3D重组基底膜覆盖与两个人DCIS细胞系MCF10.DCIS和SUM102的共培养。这两个细胞系在3D培养中形成了巨大的发育不良结构，类似于体内的DCIS，偶尔还会出现侵袭性突起。在与分泌HGF的乳腺成纤维细胞共培养中，具有侵袭性突起的DCIS结构的比例增加。用分泌HGF的成纤维细胞的条件培养液或重组HGF激活c-Met可增加DCIS结构中侵袭性突起的比例，使其降解IV型胶原，并分泌尿激酶型纤溶酶原激活物及其受体。与体外发现一致的是，与分泌HGF的成纤维细胞共注射增加了SCID小鼠MCF10.DCIS异种移植的侵袭力。我们的研究表明，成纤维细胞和侵袭前DCIS细胞之间的旁分泌HGF/c-Met信号增强了向侵袭性癌症的转化，并表明3D共培养是测试针对肿瘤微环境增强侵袭性的治疗方法的合适模型。
Stromal-derived hepatocyte growth factor (HGF) acting through its specific proto-oncogene receptor c-Met has been suggested to play a paracrine role in the regulation of tumor cell migration and invasion. The transition from pre-invasive ductal carcinoma in situ (DCIS) to invasive breast carcinoma is marked by infiltration of stromal fibroblasts and the loss of basement membrane. We hypothesized that HGF produced by the infiltrating fibroblasts may alter proteolytic pathways in DCIS cells and to study this hypothesis established 3D reconstituted basement membrane overlay co-cultures with two human DCIS cell lines: MCF10.DCIS and SUM102. Both cell lines formed large dysplastic structures in 3D cultures that resembled DCIS in vivo and occasionally developed invasive outgrowths. In co-culture with HGF-secreting mammary fibroblasts, the percentage of DCIS structures with invasive outgrowths was increased. Activation of c-Met with conditioned media from HGF-secreting fibroblasts or with recombinant HGF increased the percentage of DCIS structures with invasive outgrowths, their degradation of collagen IV and their secretion of urokinase plasminogen activator and its receptor. In agreement with the in vitro findings, co-injection with HGF-secreting fibroblasts increased invasiveness of MCF10.DCIS xenografts in SCID mice. Our study demonstrates that paracrine HGF/c-Met signaling between fibroblasts and pre-invasive DCIS cells enhances the transition to invasive carcinomas and suggests that 3D co-cultures are appropriate models for testing therapeutics that target tumor microenvironment-enhanced invasiveness.