Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells
Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells
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DOI：
10.1053/j.gastro.2004.12.036
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发表时间：
2005-04-01
期刊：
影响因子：
29.4
通讯作者：
Adler, G
中科院分区：
文献类型：
--
作者：
Bachem, MG;Sch端nemann, M;Adler, G
背景与目的：肿瘤结缔组织增生症是导管型胰腺癌的典型病理表现之一。本研究的目的是研究与胰腺癌相关的纤维化的细胞和分子机制。方法：对27例人胰腺癌和36例裸鼠皮下注射含和不含胰星状细胞的MiaPaCa2、Panc1和SW850进行免疫组织化学染色。从胰腺癌组织中分离出产生基质的细胞，并与从慢性胰腺炎组织中分离的胰腺星状细胞进行比较。本文研究了癌细胞对胰腺星状细胞的旁分泌刺激作用，包括基质合成(胶原和c-纤维连接蛋白在蛋白质和信使RNA水平)和细胞增殖(溴脱氧尿苷掺入)。结果：27例胰腺癌中有26例结蛋白和α-平滑肌肌动蛋白阳性细胞数较高。纤维连接蛋白和胶原蛋白与这些细胞相关。通过细胞细丝染色、基因表达谱和形态学检查，从胰腺癌生长的方法获得的产生基质的细胞被鉴定为胰腺星状细胞。MiaPaCa2、Panc1和SW850细胞培养上清液可刺激培养的胰星状细胞增殖、I型胶原和c-纤维连接蛋白的合成。用抗成纤维细胞生长因子2、转化生长因子β1和血小板衍生生长因子的中和抗体预先孵育癌细胞上清液，可显著降低刺激效应。皮下注射癌细胞和胰星状细胞诱发裸鼠快速生长的皮下纤维性肿瘤。癌细胞形态计量学分析(细胞角蛋白染色)显示这些肿瘤中癌细胞密度较高。结论：胰腺星状细胞在裸鼠模型中对肿瘤生长有很强的支持作用。胰腺癌结缔组织沉积增多是癌细胞旁分泌刺激胰腺星状细胞的结果。
Background & Aims: Tumor desmoplasia is one of the representative histopathologic findings in ductal pancreatic adenocarcinoma. The aims of this study were to examine the cellular and molecular mechanisms of fibrogenesis associated with pancreatic adenocarcinomas. Methods: Immunostainings were performed with human pancreatic adenocarcinomas (n = 27) and tumors induced in nude mice (n = 36) by subcutaneously injecting MiaPaCa2, Panc1, and SW850 with and without pancreatic stellate cells. Matrix-producing cells were isolated from pancreatic adenocarcinomas and compared with pancreatic stellate cells isolated from tissue of chronic pancreatitis. Paracrine stimulation of pancreatic stellate cells by carcinoma cells was studied regarding matrix synthesis (Collagen and c-fibronectin on protein and messenger RNA level) and cell proliferation (bromodeoxyuridine incorporation). Results: High numbers of desmin and a-smooth muscle actin-positive cells were detected in 26 of 27 pancreatic adenocarcinomas. Intense fibronectin and Collagen stainings were associated with these cells. By using cytofilament stainings, gene expression profiling, and morphological examinations, the matrix-producing cells obtained by the outgrowth method from pancreatic adenocarcinomas were identified as pancreatic stellate cells. Supernatants of MiaPaCa2, Panc1, and SW850 cells stimulated proliferation and collagen type I and c-fibronectin synthesis of cultured pancreatic stellate cells. Preincubation of the carcinoma cell supernatants with neutralizing antibodies against fibroblast growth factor 2, transforming growth factor beta 1, and platelet-derived growth factor significantly reduced the stimulatory effects. Subcutaneous injection of carcinoma cells and pancreatic stellate cells induced fast-growing subcutaneous fibrotic tumors in nude mice. Morphometric analysis of carcinoma cells (cytokeratin stainings) showed a high density of carcinoma cells in these tumors. Conclusions: Pancreatic stellate cells strongly support tumor growth in the nude mouse model. The increased deposition of connective tissue in pancreatic carcinoma is the result of a paracrine stimulation of pancreatic stellate cells by carcinoma cells.