Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice
Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice
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DOI：
10.1111/j.1349-7006.2006.00369.x
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发表时间：
2007-02-01
期刊：
影响因子：
5.7
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Kimura, Kenji;Satoh, Kennichi;Shimosegawa, Tooru
为了建立小鼠胰腺癌，将二甲基苯并蒽（DMBA）注入小鼠胰腺。DMBA治疗2周后胰腺切片可见管状复杂病变的形成。在给药后1个月发现异常的管状复组织并导管化生。在胰腺注射DMBA 3个月后，10只小鼠中有6只出现了视觉上可识别的肿瘤，并伴有各种类型细胞异型性的前体病变。相比之下，在安慰剂治疗的动物中没有视觉或组织学上可检测到的肿瘤。smad4、cyclin D1和p53在dmba诱导的肿瘤中的表达谱与人胰腺癌相似，提示这将是研究胰腺癌发生的形态学和分子机制的有用小鼠模型。特异性抗体免疫组化研究显示，Notch-1和Hes-1在化学诱导的胰腺肿瘤中从管状复合物到癌的病变中均有表达。微解剖的半定量逆转录聚合酶链反应表明，Notch-1的表达从前体病变到癌细胞是连续的，而Pdx-1在癌细胞中的表达与前体病变相比有所减弱。此外，γ分泌酶抑制剂N-（N-[3,5-二氟苯乙酰]- l -丙烯基）- s -苯基甘氨酸t-丁基酯抑制Notch信号通路可降低胰腺癌细胞的生长。因此，形成管状复合体需要Notch信号，其持续激活可能导致胰腺从管状复合体向癌前或恶性病变的转变以及癌细胞的发展。
To establish pancreatic cancer in mice, dimethylbenzanthracene (DMBA) was administered into mice pancreata. The formation of tubular complex lesions was found in the pancreatic sections from 2 weeks after DMBA treatment. Abnormal tubular complex formations with ductal metaplasia were found from 1 month after the administration. By 3 months after DMBA injection into the pancreas, 6 of 10 mice showed visually recognizable tumors with precursor lesions of various types of cell atypia. In contrast, there were no visually or histologically detectable tumors in the placebo-treated animals. The expression profiles of smad 4, cyclin D1 and p53 in the DMBA-induced tumors were similar to those of human pancreatic cancer, suggesting that this would be a useful mouse model for studying the morphological and molecular mechanisms involved in pancreatic carcinogenesis. Immunohistochemical study using specific antibodies revealed that Notch-1 and Hes-1 were expressed in lesions ranging from tubular complexes to carcinoma in these chemically induced pancreatic tumors. Semiquantitative reverse transcription-polymerase chain reaction with microdissection demonstrated that Notch-1 expression was continuous from precursor lesions to carcinoma cells, whereas Pdx-1 expression was attenuated in carcinoma cells compared to precursor lesions. In addition, inhibition of the Notch signaling pathway by the gamma-secretase inhibitor N-(N-[3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester reduced pancreatic cancer cell growth. Therefore, Notch signaling is required to form the tubular complexes and its continuous activation might lead to the transition from tubular complexes to premalignant or malignant lesions and carcinoma cell development in the pancreas.