title: Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai City, Miyagi, 980-8574, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kimura
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kanno
authors.forename: Shin
authors.initials: S
authors.lastname: Hamada
authors.forename: Morihisa
authors.initials: M
authors.lastname: Hirota
authors.forename: Mareyuki
authors.initials: M
authors.lastname: Endoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D015127:9,10-Dimethyl-1,2-benzanthracene; D018631:ras Proteins