[Frontiers in Bioscience 2, d271-282, June 1, 1997]

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Parviz M. Pour

The UNMC/Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE

Received 5/6/97 Accepted 6/2/97


Derivation of ductal-type adenocarcinoma from within islets could be more convincingly demonstrated if tumors could be induced in the extrapancreatic islets. This approach was achieved by transplanting the homologous pancreatic islets into the submandibular glands of hamsters (65). The submandibular gland was chosen as a site of islet transplantation because this tissue morphologically and biologically resembles the pancreas and because a pilot study demonstrated that this tissue is an ideal site for islet survival and growth (65). When hamsters with islets transplanted into their submandibular glands were treated with BOP, ductular lesions similar to those in the pancreas of these hamsters developed at the site of islet transplantation (66). However, no frank carcinoma was seen in the submandibular gland and the origin of the lesions from either submandibular gland or islets could not be determined. The small number of animals in the groups, the low dose of BOP, and the short experimental duration could have accounted for lack of cancers in these animals. To clarify these issues, in a subsequent study, islets from male hamster donors were transplanted into the right submandibular gland of female recipient hamsters who received higher doses of BOP. By transplanting male hamster islets into the submandibular glands of female hamsters, the origin of the tumor from either the male islets or the female submandibular gland could be determined by identification of the sex chromosome (Y chromosome) in the tumor cells. Six to 12 weeks after BOP treatment, 24% of hamsters developed large, aggressive, ductal/ductular type adenocarcinomas in the right submandibular gland (Fig. 10), where islets were transplanted. On the other hand, no tumors were found in the left submandibular gland, where either immortal hamster pancreatic ductal cells, fragments of hamster thyroid tissue, or cellulose powder were injected (67). As in the pancreas of BOP-treated hamsters, these islets exhibited intrainsular ductular or cyst formation (Fig. 11) and expression of blood group A antigen, which is a pancreatic-tumor-associated antigen in this species (39,40). Many tumor cells adjacent to islets reacted with anti-insulin or with both anti-insulin and anti-blood group A. Similar to the primary pancreatic cancer, tumors in the submandibular gland showed the c-Ki-ras mutation in codon 12 (67). A Y chromosome mRNA, identified by PCR, clearly pointed to the derivation of the tumors from male islet tissue. The possibility that tumors may have originated from a few ductular or acinar cells attached to the transplanted islets was ruled out since ultrastructural examination of many islets before transplantation did not reveal their presence. Moreover, transplantation of immortal pancreatic ductal cells that could be readily transformed in vitro and could give rise to invasive cancers in vivo, did not produce tumors in the submandibular gland (68).

Fig. 10. Induction of tumors by BOP in the submandibular glands in hamsters, where homologous islets were transplanted. (From reference 67 ,with permission)

Fig. 11. Hyperplastic ductular elements are seen among islets. Some of the cells lining the ductules reacted with anti-insulin (not shown) H&E, X 210.