Transgenic mice carrying a murine amylase 2.2/SV40 T antigen fusion gene develop pancreatic acinar cell and stomach carcinomas.
The mouse pancreatic amylase Amy-2.2 gene was fused to the structural gene for SV40 T antigen, and 51 independent transgenic founder mice carrying the fusion gene were generated. The majority of the founders and 100% of their offspring in the derived transgenic lines developed pancreatic acinar cell carcinomas and stomach carcinomas. Transgenic animals also had a high incidence of metastatic carcinomas in other tissues. The development of stomach carcinomas was unexpected because the Amy-2.2 promoter was not previously known to be expressed in stomach. Northern blot analyses and ribonuclease protection assays showed that Amy-2.2 is expressed in stomach, at approximately 0.05% of the level in pancreas. Expression of the fusion gene in stomach, therefore, appears to represent a previously unrecognized activity of the Amy-2.2 promoter. Examination of young transgenic mice demonstrated that preneoplastic lesions were present in pancreas and stomach before the development of neoplastic lesions in either tissue, consistent with the notion that stomach neoplasms are primary neoplasms and not metastases from the pancreas. Ribonuclease protection assays demonstrated that properly initiated large T and small t antigen transcripts were present in pancreas and stomach during tumorigenesis. T antigen protein was also detected in pancreas and stomach by immunohistochemistry. A time course for tumorigenesis was established for several transgenic mouse lines in which distinct types of lesions appeared at predictable times. This study provides the basis for future analysis of the role of SV40 T antigen in the progression and maintenance of pancreatic and stomach carcinomas.
Ceci
J D
JD
Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21701.
Kovatch
R M
RM
Swing
D A
DA
Jones
J M
JM
Snow
C M
CM
Rosenberg
M P
MP
Jenkins
N A
NA
Copeland
N G
NG
Meisler
M H
MH
D000681:Amylases / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics*; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D003001:Cloning, Molecular; D005753:Gastric Mucosa / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D014158:Transcription, Genetic
D000952:Antigens, Polyomavirus Transforming; D000681:Amylases