Pancreatic tumors that are similar in morphology and biologic behavior to those in man can be induced in adult Syrian golden hamsters by N-nitrosobis(2-oxoproply)amine (BOP) and related compounds. In our recent study we found that pancreatic tumors were induced in the offspring of dams treated with 10 mg/kg b.w. each BOP at the 8th, 10th, 12th and 14th day of their pregnancy. However the incidence of pancreatic lesions in the offspring were low, most probably because we had to terminate the experiment early. Interestingly 2 of the induced tumors resembled human pancreatoblastomas, which occur in young individuals. A literature survey has indicated the occurrence of pancreatic cancer in some families and in children of parents with certain occupations. Based on these data, we offer the hypothesis that the rising incidence of pancreatic cancer is due, in part, to initiation of carcinogenesis during intrauterine life and its promotion by as yet unknown environmental factors during postnatal life. To test this hypothesis we propose to investigate the effects of BOP in dams at different times during gestation. By this experimental protocol a high tumor incidence is expected. The proposed study will, at the same time, address the histogenesis of pancreatic cancer (from ductal/ductular or acinar cells) in our model, as our embryological studies have revealed that the organogenesis of the fetal pancreas begins at the 8th day of the gestation period and acinar cells are not formed until the 14th day of gestation (one day prior to the birth). Accordingly the origin of pancreatic cancer can be substantiated by administering BOP between the 8th and 13th day of gestation when no acinar cells will have developed or at the time of acinar cell development (at the 14th day of gestation). Immunohistologic studies with defined monoclonal antibodies, which have been shown by us to detect selectively either the induced pancreatic tumors or hamster acinar cells, will be employed for further clarification of the histogenesis of tumors in the offspring. Overall the proposed experiment will answer the following questions: 1) At which stage of pancreas organogenesis is the pancreas responsive to carcinogenesis? 2) Will the morphology of induced tumors vary with treatment time, i.e. induction of ductal/ductular or acinar cell neoplasms? The results of these experiments will aid greatly in our understanding of pancreatic carcinogenesis and could be helpful in the consideration of preventive measures.
| MacDougall, J R; Bani, M R; Lin, Y et al. (1995) The 92-kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. Cancer Res 55:4174-81 |
