Evolution of the expression of fetal acinar antigens during carcinogenesis of the pancreas in hamsters: individual follow-up by open biopsy.

Individual lesions in the pancreas and the presence of fetal acinar antigens along with carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (CAS: 60599-38-4) were studied by open biopsy in 16 Syrian golden hamsters 13, 22, and 40 weeks after initiation of treatment. At 13 weeks, cystadenoma and regular ductal hyperplasia were noted in 3 animals and 1 animal, respectively. Staining for fetal acinar antigens in the pancreas was found in 69% of the hamsters. At 22 weeks, cystadenoma and hyperplastic ducts were common (60 and 53%), and 3 hamsters developed pancreatic adenocarcinoma. Fetal acinar antigens persisted in the acini and extended to irregular hyperplastic ducts and tumor cells. At 40 weeks, ductal proliferation was the main lesion in all pancreatic tissue, and 9 animals had adenocarcinoma. Acinar antigens were found in the remaining acini, in irregular hyperplastic ducts, and in tumor cells. Thus, once reexpressed, fetal acinar antigens persist in pancreatic lesions and pancreatic carcinomas in the hamster.

Isolation and characterization of two oncofetal glycoproteins from hamster pancreas using concanavalin A and preparative electrophoresis.

Pancreatic fetal acinar antigens in the Syrian golden hamster, which are associated with development of the pancreas, have been previously described. In this study, two major antigens were isolated from fetal pancreas using affinity chromatography on Con A-Sepharose and preparative electrophoresis. Homogenates from fetal and adult pancreas were analyzed for their ability to bind to concanavalin A. This lectin allowed obtention of eluted fractions accounting for 2 and 0.7%, respectively, of the protein content in crude extracts. Concanavalin A-positive fraction from fetal pancreas contained two major carbohydrate-reactive glycoproteins of relative molecular weight (Mr) 80 000 and 58 000 in SDS-polyacrylamide gel electrophoresis. Both behaved as fetal antigens in nitrocellulose blot immunoassay. Similar experiments with chemically induced tumors of the pancreas led to a concanavalin A fraction containing the 80 and 58 kDa fetal glycoproteins; but in this case, the fraction was quite heterogeneous. Our data provide new support for the existence of differentiation antigens in the acinar cells of the pancreas, and indicate that two major ones are glycoproteins. Moreover, both are expressed in pancreatic tumors.

[Oncofetal proteins of the exocrine pancreas]. / Protéines oncofoetales du pancréas exocrine.

Specific pancreatic oncofetal proteins have been discovered in man and a species of hamster using polyclonal antisera against fetal pancreatic extracts. Two main components in the Mr range of 80 kDa and 58 kDa (hamster) and 110 kDa and 58 kDa (man) were detected in pancreatic fetal extracts, by the "Western blot" technics. Two monoclonal antibodies, namely J28 directed against the human 110 kDa component (FAP protein) and B4 directed against the hamster 58 kDa component (FP protein) have been prepared. The B4 cross-reacts with the homologous human antigen. These monoclonal antibodies have shown that both proteins are antigenically unrelated, although they share common properties such as association to development of exocrine pancreas and high tissue specificity. The expression of both proteins increases in the case of pancreatic cancer but localisation varies. FAP protein is found in peritumoral acinar tissue, whereas FP protein is expressed in transformed cells. FAP protein is a serum marker for pancreatic pathologies and combined with CA 19-9 antigen assay it provides a serum test which is almost specific for cancer of the pancreas with near 100% sensitivity.

Expression of oncofoetal pancreatic antigens in hamster adult pancreas during experimental carcinogenesis.

Foetal acinar components associated with the development of the hamster pancreas have been previously defined with the aid of an antifoetal pancreas serum. In immunohistology this antiserum also stained malignant ductal cells in N-nitrobis (2-oxopropyl) amine (BOP)-induced pancreatic adenocarcinoma. It did not stain adult pancreas structures including acini, ducts and islets of Langerhans. In this study, re-expression of foetal acinar antigens was disclosed before formation of tumours. Adenocarcinomas were not detected by conventional histology before the 24th week following initiation of the chemical treatment. However, staining with the antiserum was observed from the 7th week appearing in the apex of some acini cells having an almost normal histological appearance. Later, foetal acinar expression was frequently associated with evident morphological alterations in acini like dyskaryosis, enlarged cytoplasm or lumina. Staining of ducts with marked atypical epithelium and (as already reported) of neoplastic ducts was also observed. It was not detected in other pancreatic lesions viz. cystadenomas, mucoid glands and regular hyperplastic ducts. Acinar dedifferentiation as assessed by expression of foetal components preceded formation of tumours in all instances.

Ultrastructural changes in acinar cells of hamster pancreas in chemically induced carcinogenesis.

Ultrastructural changes arising in the pancreas of the Syrian golden hamster after treatment with N-nitrosobis (2-oxopropyl) amine (BOP) were studied at short intervals. Alterations were found in acinar cells i.e. loss of zymogen granules, dilatation of granular endoplasmic reticulum, depolarization, irregular nucleus and separation of lateral surfaces (intermembranary spaces). As a result, the compact morphology of normal acini switched towards a new structure resembling a pseudo-ductule. Such alterations occurred from the 3rd month and preceded tumor formation. It is noteworthy that ducts and islets of Langerhans appeared unaltered in all instances. These results are consistent with the hypothesis that BOP induced pancreatic adenocarcinoma in hamsters originates in the acinar cell.

The diagnostic value of the foetoacinar pancreatic (FAP) protein in cancer of the pancreas; a comparative study with CA19/9.

The serum diagnostic value of the foeto-acinar pancreatic protein (FAP protein), an oncofoetal pancreatic antigen, was tested in 201 patients. Of these, 112 suffered from malignant disease (57 patients had pancreatic carcinoma and 55, extra-pancreatic malignancies) and 89 had benign disease (49 patients with hepato-pancreato-biliary disease and 40 with other benign disease). FAP protein was measured by a competitive radioimmunoassay. In this technique, the normal cut-off level was 10% inhibition. This was deducted from values in 32 normal sera. FAP protein levels superior to 10% inhibition were found in 86% of patients with pancreatic cancer, in 31% with non-pancreatic malignancy, in 69% with benign hepato-pancreato-biliary disease and in 20% with other benign diseases. Accordingly, sensitivity of FAP protein for pancreatic carcinoma was 86% and specificity, 66%. However, high FAP protein levels (greater than 30% inhibition) were almost exclusively seen in patients with pancreatic cancer. At this cut-off level, specificity increased to 95% but sensitivity decreased to 51%. Determination of the carbohydrate antigen CA19/9 was made in parallel by a commercially available assay. At the cut-off level of 37 u ml-1, CA19/9 in our serum panel had a sensitivity of 74% for pancreatic carcinoma and a specificity of 88%. In pancreatic cancer 55 out of 57 patients had elevated levels of either FAP protein or CA19/9 (sensitivity; 96%).

Detection of pancreas pretumoral stage by means of organ transplantation.

Syrian golden hamsters were treated at monthly intervals for three months with N-nitrosobis (2-oxopropyl) amine (BOP) at doses of 20 mg/kg. During the treatment program individual pancreases were analysed by histology and transplanted into syngeneic recipients. Within the first 20 weeks following BOP administration, only a few alterations in the acinar cells were detected histologically. Nevertheless, pancreases taken as early as 10 weeks following the initiation of the chemical treatment produced local tumors at the site of subcutaneous implantation. Tumors thus obtained by graft were noted to be carcinomas of ductal type. Organ transplantation was thus observed to be a good method of detecting early neoplastic transformations in the pancreas which were not seen by conventional histology.