Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Abstract

Abstract. N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic ductal carcinomas and early ductal lesions in Syrian hamsters have been reported to show histopathological resemblance to those in humans. Specific protein expression profiles have been found in human carcinomas, but a detailed molecular approach regarding the dissection of BOP-induced pancreatic carcinogenesis has yet to be determined. The present immunohistochemical study of early and advanced hamster lesions focused on five proteins reported to be overexpressed in human patients, to clarify interspecies phenotype similarity. Integrin α V β 3 was found to be overexpressed in the epithelial cells of 13 of 14 atypical hyperplasias and 6 of 6 adenocarcinomas. This overexpression was more frequent than in the remaining four proteins. However, immunoreactivity for α-enolase in epithelial cells and for kallikrein 7 and galectin-1/3 in both epithelial and stromal cells was also evident at various frequencies. Thus, similarities of tumor-associated protein expression between human and hamster pancreatic ductal lesions were confirmed, and integrin α V β 3 was identified as a potentially useful immunohistochemical marker for early lesions in hamsters. IntroductionPancreatic cancer is among the 10 most frequently occurring type of cancer. In Japan, pancreatic cancer is ranked fifth as a cause of cancer-related mortality. The mortality rate associated with this type of cancer also ranks high in other developed countries (1,2). The detection of pancreatic cancer at early operable stages is difficult, combined with the lack of curative treatment approaches other than complete surgical removal; thus, 5-year relative survival rates are less than 6% (3,4). Therefore, it is crucial to develop new diagnostic and preventive methods to complement any improvements in therapeutic methods for the reduction of mortality and morbidity, and to explore specific proteins overexpressed in early lesions during pancreatic carcinogenesis.Specific protein expression profiles revealed by immunohistochemical and proteomic analyses are currently employed in the application of individualized therapy of advanced human pancreatic carcinomas (5-8). Consequently, a number of candidates of prognostic and/or predictive markers have been established (9,10). Examples expressed in early lesions show potential for the development of novel diagnostic and preventive strategies.Chemically induced and transgenic animal models for pancreatic ductal carcinogenesis have been the target of investigation of the impact of environmental factors and the role of specific gene alterations in multistage carcinogenesis (11)(12)(13)(14)(15). Among the models established thus far, the N-nitrosobis(2-oxopropyl)amine (BOP)-induced hamster model is the first and most widely utilized based on similarities to human diseases in the morphological characteristics of, not only advanced cancers, but also early ductal lesions, as well as pivotal genetic alterations, including K-ras and p16 (13,(16)(17)(18). In particular...

In Vivo SPECT Imaging with 111In-DOTA-c(RGDfK) to Detect Early Pancreatic Cancer in a Hamster Pancreatic Carcinogenesis Model

“…This model provides unique characteristics that are similar to a sequence of well-characterized morphologic changes in the human pancreatic duct and frequently shows point mutations in codon 12 of the K-ras gene, in accordance with human findings (23,24). We found that a v b 3 -integrin was overexpressed not only in adenocarcinomas but also in atypical hyperplasia in this hamster model (25). Therefore, this model is useful in the development of imaging probes for the early detection of pancreatic carcinogenesis.…”

Biphasic Alterations in Expression and Subcellular Localization of MUC1 in Pancreatic Ductal Carcinogenesis in Syrian Hamsters

“…The extrapancreatic common bile duct and ampulla of Vater were ligated before the dye was injected to prevent it from effluxing into the liver and duodenum. 24 Pancreatic ducts were isolated using micro scissors, forceps, and scalpels under a stereomicroscope (Fig.…”

“…16,17 Another animal model, hamster pancreatic ductal carcinogenesis induced by N-nitrosobis(2-oxopropyl)amine (BOP), has been extensively studied because of similarities in morphological changes and common genetic alterations, such as KRAS and p16 genes, with humans and the convenience of the carcinogen treatment and handling. 24 On the basis of these genetic, histomorphological, and immunohistochemical profiles, the hamster model was considered to be adequate for investigating molecular profiles, especially in the early lesions of pancreatic carcinogenesis. 23 In our recent study, several proteins, which were previously reported to be up-regulated in human IDCs of the pancreas and involved in cell-to-cell or cell-to-matrix interactions, were similarly confirmed to be expressed not only in IDCs but also in early lesions in hamsters.…”

Modifying effects of 1,2-dichloropropane on N-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinogenesis in male Syrian hamsters

“…Preneoplastic and neoplastic ductal lesions in the pancreas were diagnosed as atypical ductal hyperplasia and pancreatic ductal adenocarcinoma, respectively (Pour et al, 1981;Takahashi et al, 2008;Kitahashi et al, 2011;Okamura et al, 2013). Atypical ductal hyperplasias in the pancreas were characterized by proliferation of the duct epithelium with minimal to moderate cellular atypia, with or without mucous metaplasia.…”