Carcinogenesis, Vol. 20, No. 2, 317-324,
February 1999
© 1999 Oxford University Press
Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro
1 UNMC/Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA,
2 Visceral and Transplantation Surgery, Inselspital, Bern, Switzerland,
3 The University of Texas Health Science Center, Center for Human Cell Biotechnology, San Antonio, TX, USA,
4 Klinik für Gastroenterologie, Hepatologie und Infektiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany and
5 Munroe-Meyer Center for Human Genetics,
6 Department of Biochemistry and Molecular Biology and
7 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
Our previous studies in the hamster pancreatic cancer model have indicated that pancreatic ductal adenocarcinomas derive not only from ductal/ductular cells but also from islets. To verify the presence of carcinogen-responsive cells within islets, we tested the effect of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) on recently established continuous hamster pancreatic islet culture. Isolated pure pancreatic islets of hamsters were treated in vitro with BOP at a concentration of 0.25 mM three times a week for 19 weeks. Each treatment week was designed as a stage. The growth of these cells, designated KL5B, was compared with untreated cultured islets, designated KL5N. As in our previous study, between 14 and 21 days of culture, exocrine and intermediary cells developed within both KL5N and KL5B islets, which were then replaced by undifferentiated cells. No differences were found in the growth patterns of KL5N and KL5B until stage 4, when KL5B cells showed accelerated cell growth and cell pleomorphism, which increased gradually at later stages of treatment. Anchorage-independent and in vivo growth did not appear until stage 19. Mutation of c-Ki-ras at codon 12 (GGT
GAT) was detected in KL5B cells but not in KL5N cells. In vivo KL5B cells formed anaplastic invasive cancer with areas of glandular formation, overexpressed TGF-
and EGFR, expressed cytokeratin, vimentin, laminin and -1 antitrypsin and reacted strongly with L-phytohemagglutinin and tomato lectin. Some cells within islets are responsive to the carcinogenic effects of BOP. Whether these cells represent islet cell precursors (stem cells) or malignant transdifferentiated islet cells remains to be seen.
Abbreviations: BOP, N-nitrosobis(2-oxopropyl)amine; SMG, submandibular gland; PHA, phytohemagglutinin.
8 To whom correspondence should be addressed at: UNMC/Eppley Cancer Center, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA Email: ppour{at}mail.unmc.edu
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