Molecular differences between human and experimental pancreaticobiliary diversion-induced

A series of molecular changes are now known to be seen in human pancreatic neoplasia, including the very frequent mutational activation of Kirsten ras oncogene at codon 12, overexpression of the epidermal growth factor receptor, and abnormalities of c-erbB-2 expression. In order to determine whether similar changes can be seen in animal models of pancreatic cancer a molecular analysis of tumours induced in rats by pancreaticobiliary diversion was performed. The polymerase chain reaction was used to amplify portions of the rat Kirsten ras gene and sequence specific oligonucleotide hybridisation was used to define whether sequences were wild type or mutant. No evidence of mutation was found in the Kirsten ras gene at codons 12 or 61, where activating mutations are known to occur. In addition immunohistochemical methods were used to investigate expression of c-erB-2 and the epidermal growth factor receptor but no evidence of abnormal expression was found. We conclude that there are major molecular differences between human and experimental rat pancreatic cancer. ICRF Molecular Oncology Group, Hammersmith Hospital, London PA Hall N R Lemoine ICRF Histopathology Unit, Lincoln's Inn Fields, London P A Hall Gastroenterology Unit, Guy's Campus, UMDS, London G Murphy R H Dowling Correspondence to: Dr Peter A Hall, Department of Histopathology, Royal Postgraduate Medical School, Du Cane Road, London W12 ONN. Accepted for publication June 1990 There is considerable evidence to support the notion that multiple genetic events are necessary for neoplastic transformation'2 and several complementary molecular abnormalities have been described in human pancreatic cancer. Firstly, the Kirsten ras gene is mutated at codon 12 in up to 90% of cases.3'8 Secondly, the c-erbB2 proto-oncogene, which is closely related in sequence and structure to the epidermal growth factor receptor,910 is overexpressed in at least 20% of patients." Thirdly, the epidermal growth factor receptor (c-erbB-1) is abnormally expressed in 30 to 50% of pancreatic cancers.'2 13 Finally, there is evidence that the potential ligands for the epidermal growth factor receptor, transforming growth factor a, and epidermal growth factor are expressed by pancreatic tumour cells'4 and thus may form an autocrine loop. 5 16 Several animal models of pancreatic cancer have been described.'7 In the rat, morphological changes including the progressive formation of hyperplastic nodules, adenomas, and the eventual development of overt malignancy can be induced by treatment with carcinogens such as azaserine. It has previously been reported that pancreaticobiliary diversion can induce hypercholecystokininaemia, pancreatic hyperplasia, and ultimately after 15 to 24 months, neoplasia that is morphologically very similar to that seen in the azaserine model. 1820 It is not known if the oncogenic events in the animal models resemble those in human pancreatic cancer and consequently we have investigated the pancreaticobiliary diversion model using the polymerase chain reaction and sequence specific oligonucleotide hybridisation to detect mutational activation of the Kirsten ras oncogene and immunohistochemistry to detect abnormalities of expression of the c-erbB-2 proto-oncogene and the epidermal growth factor receptor.