Open AccessMature acinar cells are refractory to carcinoma development by targeted activation of Ras oncogene in adult rats
Author(s) -
Tanaka Hajime,
Fukamachi Katsumi,
Futakuchi Mitsuru,
Alexander David B.,
Long Ne,
Tamamushi Shojiro,
Minami Kohtaro,
Seino Susumu,
Ohara Hirotaka,
Joh Takashi,
Tsuda Hiroyuki
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01410.x
Subject(s) - cre recombinase , kras , transgene , oncogene , acinar cell , cancer research , genetically modified mouse , biology , pancreas , pancreatic cancer , hras , pathology , medicine , endocrinology , cell , cancer , gene , cell cycle , colorectal cancer , biochemistry , genetics
Pancreatic ductal adenocarcinoma (PDA) is one of the most debilitating malignancies in humans. A thorough understanding of the cytogenesis of this disease will aid in establishing successful treatments. We have developed an animal model which uses adult Hras G12V and Kras G12V transgenic rats in which oncogene expression is regulated by the Cre/loxP system and neoplastic lesions are induced by injection of adenovirus‐expressing Cre recombinase. When adenovirus with Cre recombinase under the control of the CMV enhancer/chicken β‐actin (CAG) promoter (Ad‐CAG‐Cre) is injected into the pancreatic duct of these animals, pancreatic neoplasias develop. Pathologically, the origin of these lesions is duct, intercalated duct, and centroacinar cells, but not acinar cells. The present study was undertaken to test the effect of acinar cell‐specific oncogenic ras expression. Adult transgenic rats were injected with adenovirus with Cre recombinase under the control of the acinar cell‐specific promoters amylase (Ad‐Amy‐Cre) and elastase‐1 (Ad‐Ela‐Cre) or under the control of the non‐specific CAG promoter. Injection of either Ad‐Amy‐Cre or Ad‐Ela‐Cre into the pancreatic ducts of transgenic animals in which oncogenic Kras is tagged with hemagglutinin (HA), HA‐Kras G12V rats resulted in expression of oncogenic ras in acinar cells but not in duct, intercalated duct, or centroacinar cells. Notably, injected animals did not develop any observable proliferative or neoplastic lesions. In marked contrast, injection of Ad‐CAG‐Cre resulted in pancreatic cancer development within 4 weeks. These results indicate that adult acinar cells are refractory to Ras oncogene activation and do not develop neoplasia in this model. ( Cancer Sci 2009)