Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression
Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression
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DOI：
10.1593/neo.08330
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Fischer, Susan M.
中科院分区：
文献类型：
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作者：
Colby, Jennifer K.;Klein, Russell D.;Fischer, Susan M.
环氧合酶-2 （COX-2）过表达是多种组织中慢性炎症与化生和肿瘤变化相关的一个确定因素。我们产生了转基因小鼠（BK5）。COX-2)，其中COX-2及其效应物的升高引发外分泌胰腺的化生-不典型增生序列。组织学评估显示慢性胰腺炎样状态，以腺泡到导管化生和血管化良好的纤维炎性间质为特征，3个月后发展。6至8个月时，在化生的导管中出现强烈的发育不良特征，提示胰腺导管腺癌。增殖增加，细胞异型性和正常细胞/组织组织的丧失是转基因胰腺的典型特征。使用免疫组织化学检测与人类炎症性和肿瘤性胰腺疾病相关的生物标志物的改变。异常胰腺表型可以通过维持含有塞来昔布（一种表征良好的COX-2抑制剂）的小鼠饮食来完全预防。尽管有高度的异型性，但仅观察到有限的侵犯邻近组织的证据，没有远处转移的证据。然而，当注射到同基因小鼠或裸鼠体内时，来自自发病变的细胞系具有侵袭性致瘤性。在该模型中观察到的化生/发育不良变化的进行性使其成为检查从慢性炎症到肿瘤转变的有价值的工具。
Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5. COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.