Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma
Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-03-0825
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发表时间：
2004-11-01
影响因子：
11.5
通讯作者：
Iredale, JP
中科院分区：
文献类型：
--
作者：
Armstrong, T;Packham, G;Iredale, JP
目的：本研究旨在确定胰腺癌细胞与胰腺星状细胞（PSCs）之间的功能性相互作用在胰腺癌促结缔组织增生反应（DR）形成中的作用，并描述Ⅰ型胶原蛋白（DR的主要成分）对胰腺癌细胞表型的影响。
实验设计：采用免疫组织化学方法在胰腺癌切片中鉴定PSCs和Ⅰ型胶原蛋白，并研究它们的解剖学关系。在一系列组织培养模型中研究胰腺癌细胞系（MIA PaCa - 2、Panc - 1和AsPC - 1）、人PSCs原代培养物以及Ⅰ型胶原蛋白之间的相互作用。
结果：在体内，DR导致正常胰腺严重变形，使癌细胞与大量PSCs和丰富的Ⅰ型胶原蛋白紧密接触。在胰腺癌组织培养模型中，各细胞系的条件培养基使PSCs的[H - 3]胸腺嘧啶核苷掺入量比对照增加高达6.3倍，AsPC - 1细胞还使PSCs的胶原蛋白合成增加1.3倍。在克隆形成试验中，观察到Ⅰ型胶原蛋白可使经5 - 氟尿嘧啶处理的胰腺癌细胞的长期存活率提高高达62%。这是因为Ⅰ型胶原蛋白增加了癌细胞的增殖（[3H]胸腺嘧啶核苷掺入量比在组织培养塑料上培养的细胞高高达2.8倍），并减少了AsPC - 1细胞对5 - 氟尿嘧啶的凋亡反应（通过调节mcl - 1）。
结论：这些实验阐明了胰腺癌中DR可能形成的一种机制，并且通过其中的胶原蛋白促进胰腺癌细胞的恶性表型，提示对宿主有显著危害。
Purpose: The purpose of this study was to determine the role of functional interactions between pancreatic cancer cells and pancreatic stellate cells (PSCs) in the formation of the desmoplastic reaction (DR) in pancreatic cancer and to characterize the effect of type I collagen (the predominant component of the DR) on pancreatic cancer cell phenotype.Experimental Design: PSCs and type I collagen were identified in sections of pancreatic cancer using immunohistochemistry, and their anatomic relationship was studied. Interactions among pancreatic cancer cell lines (MIA PaCa-2, Panc-1, and AsPC-1), primary cultures of human PSCs, and type I collagen were investigated in a series of tissue culture models.Results: In vivo, the DR causes gross distortion of normal pancreas, bringing cancer cells into close contact with numerous PSCs and abundant type I collagen. In tissue culture models of pancreatic cancer, conditioned media from each cell line increased PSC [H-3]thymidine incorporation up to 6.3-fold that of controls, and AsPC-1 cells also increased PSC collagen synthesis 1.3-fold. Type I collagen was observed to increase long-term survival of pancreatic cancer cells treated with 5-fluorouracil, by up to 62% in clonogenic assays. This was because type I collagen increased the proliferation of cancer cells ([3 H]thymidine incorporation was up to 2.8-fold that of cells cultured on tissue culture plastic) and reduced apoptosis of AsPC-1 cells in response to 5-fluorouracil (by regulating mcl-1).Conclusions: These experiments elucidate a mechanism by which the DR in pancreatic cancer may form and, via the collagen within it, promote the malignant phenotype of pancreatic cancer cells, suggesting significant detriment to the host.