Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial-mesenchymal transition-like state in breast cancer cells in vitro
Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial-mesenchymal transition-like state in breast cancer cells in vitro
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DOI：
10.1242/jcs.072900
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发表时间：
2010-10-15
影响因子：
4
通讯作者：
Cho, Nam Hoon
中科院分区：
文献类型：
--
作者：
Gao, Ming-Qing;Kim, Baek Gil;Cho, Nam Hoon
从人乳腺癌的肿瘤负荷区、远端正常区以及肿瘤与正常组织之间的界面区组织中提取成纤维细胞，将相应的成纤维细胞命名为癌症相关成纤维细胞（CAF）、正常区成纤维细胞（NF）和界面区成纤维细胞（INF）。使用体外直接共培养模型评估三种类型的成纤维细胞和乳腺癌细胞之间的串扰。我们发现，与 NF 和 CAF 相比，INF 生长更快，成纤维细胞活化蛋白表达水平更高。与 CAF 和 NF 相比，与乳腺癌细胞一起生长的 INF 在诱导癌细胞中上皮-间质转化 (EMT) 方面明显更有效，如波形蛋白和 N-钙粘蛋白的诱导以及 E-钙粘蛋白的下调所示。这一 EMT 过程还伴随着细胞外信号调节激酶 (ERK) 的激活和膜 1 型基质金属蛋白酶 (MT1-MMP) 表达的调节。此外，与 NF 和 CAF 相比，INF 更大程度地促进乳腺细胞迁移。总而言之，这些发现表明，从肿瘤界面区分离的 INF 表现出比从同一肿瘤组织的正常和肿瘤区分离的 NF 和 CAF 更强大的生物调节活性，这表明肿瘤的界面区代表了对肿瘤进展至关重要的动态区域。
Fibroblasts were extracted from tissue in tumor burden zones, distal normal zones and interface zones between tumor and normal tissue of human breast carcinomas, and the corresponding fibroblasts were designated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). The crosstalk between three types of fibroblasts and breast cancer cells was evaluated using an in vitro direct co-culture model. We found that INFs grew faster and expressed higher levels of fibroblast activation protein than did NFs and CAFs. Compared with CAFs and NFs, INFs grown with breast cancer cells were significantly more effective in inducing an epithelial-mesenchymal transition (EMT) in cancer cells, as indicated by induction of vimentin and N-cadherin and downregulation of E-cadherin. This EMT process was also accompanied by activation of extracellular signal-regulated kinase (ERK) and modulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression. Additionally, INFs promoted breast cell migration to a larger extent compared with NFs and CAFs. Taken together, these findings indicate that INFs isolated from the tumor interface zone exhibited more robust biological modulatory activity than did NFs and CAFs isolated from normal and tumor zones of the same tumor tissue, suggesting that the interface zone of the tumor represents a dynamic region vital to tumor progression.