In vitro induction of ductal-type adenocarcinoma from hamster's islets by the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amnine (BOP)

To confirm the in vivo studies that induced pancreatic ductal cancers in Syrian hamsters also arise from islets, freshly isolated islets were cultured in a defined culture medium (InCell™ Corp.) containing BOP at a concentration of 0.25 mM (KL5B islets). Control islets were not treated with BOP (KL5N islets). The three-day BOP treatment was designated as "stage" and was repeated 19 times. Between 14 and 28 days of culture, ductular, acinar, and intermediary cells were formed within islets in both KL5B and KL5N. However, after day 35, these cells gave room to undifferentiated cells that reacted with antibodies against cytokeratins 14, 17, 18, carbonic anhydrase II, laminin, vimentin, tomato lectin, L-PHA, TGF-α, EGFR, and α-1-antitrypsin but not against islet hormones. After stage 19, the KL5B cells grew much faster than KL5N cells, formed colonies in soft agar and invasive and metastasizing ductal-type cancers in hamsters and nude mice. These cells, but not those of KL5N, had c-Ki-ras mutation in codon 12. We conclude that 1) a long-term islet culture can be established in an appropriate medium, 2) cultured islets can be transformed into ductal-type cancer, and 3) this process is associated with the mutation of the c-Ki-ras oncogene.