Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro

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-responsiv e cells within islets, we tested the effect of the pancreatic carcinogen N- nitrosobis(2-oxopropyl)amine (BOF) on recently established continuous hamst er pancreatic islet culture. Isolated pure pancreatic islets of hamsters we re treated in vitro with BOP at a concentration of 0.25 mM three times a we ek 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 cultu re, exocrine and intermediary cells developed within both KL5N and KL5B isl ets, which were then replaced by undifferentiated cells. No differences wer e found in the growth patterns of KL5N and KL5B until stage 4, when KL5B ce lls showed accelerated cell growth and cell pleomorphism, which increased g radually at later stages of treatment, Anchorage-independent and in vivo gr owth 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. bt vivo KL5B cells formed anaplastic invasive cancer with areas of glandular formation, overex pressed TGF-alpha and EGFR, expressed cytokeratin, vimentin, laminin and al pha-1 antitrypsin and reacted strongly with L-phytohemagglutinin and tomato lectin, Some cells within islets are responsive to the carcinogenic effect s of BOP, Whether these cells represent islet cell precursors (stem cells) or malignant transdifferentiated islet cells remains to be seen.