Promoting Effect of a High-Fat/High-Protein Diet in DMBA-Induced Ductal Pancreatic Cancer in Rats

Abstract

ObjectiveTo investigate whether a high-fat/high-protein diet (HFPD) acts as a promoter of the natural course of cancer growth in the 7,12-dimethylbenzanthracene (DMBA)-induced ductal pancreatic cancer model in rats. Summary Background DataDMBA implantation to the rat pancreas induces ductal adenocarcinoma. Information regarding the effects of diet and the presence of K-ras mutation in this model is not available. MethodsRats were randomly assigned to regular rat chow or a diet with a 30% content in fat and protein (HFPD). The presentation of cancer, the histologic spectrum of neoplasia at 1 and 9 months, and the prevalence of cancer in relation to diet were assessed. Histologic specimens comprising normal ducts, hyperplasia, dysplasia/carcinoma in situ, or carcinoma were designated by a pathologist and microdissected. Genomic DNA was extracted, and K-ras and H-ras gene mutations were determined by a mutant-enriched polymerase chain reaction assay and direct sequencing. ResultsRats fed HFPD increased their weight significantly compared with controls. DMBA induced characteristic stages of neoplasia at the implant site but not elsewhere. Macroscopic cancers of the pancreatic head presented regularly with common bile duct and gastric outlet obstruction. The prevalence of K-ras mutations was proportional to the degree of epithelial abnormality. K-ras mutations were significantly more frequent in cancer than in normal and hyperplastic ducts. H-ras mutations were not found. At 1 month in the HFPD-fed rats, the prevalence of cancer (16%) and dysplasia (16%) was not significantly different from the prevalence of cancer (29%) and dysplasia (8%) in the chow-fed rats. At 9 months the prevalence of cancer in the HFPD-fed rats increased to 29%, whereas that in the chow-fed rats decreased to 17%. The combined prevalence of cancer and dysplasia at 9 months in the HFPD-fed rats (34%) significantly exceeded that in the chow-fed rats. ConclusionsDMBA induces characteristic stages of neoplasia in the evolution of ductal pancreatic cancer in rats. K-ras mutations occur progressively in the ladder of oncogenesis, as in human pancreatic neoplasms. The addition of a diet with a high fat and protein content acts as a promoter of carcinogenesis, possibly by interfering with repair mechanisms and natural regression of early lesions.Our understanding of the development of early stages of pancreatic cancer and of the molecular mechanisms in pancreatic carcinogenesis is incomplete. The analysis of precursor lesions of pancreatic cancer in humans is limited by its recognition only at advanced tumor stages in more than 95% of patients. Mucinous cystic neoplasms and intraductal papillary mucinous tumors of the pancreas, which may serve as surrogate models of pancreatic carcinogenesis, display an evolutionary spectrum of neoplasia, including stages of dysplasia and cancer, and analysis of these tumors indicates that certain oncogenic molecular changes are as-

Dietary Mutagen Exposure and Risk of Pancreatic Cancer

“…The median level of PhIP, MeIQx, BaP, and DiMeIQx among controls was 118.4, 32.6, 37.3, and 1.8 ng/day, respectively, which were comparable to previously reported values in studies conducted among U.S. populations (26)(27)(28)(29)(30). The daily intake of the various dietary mutagens and the mutagenic index were significantly correlated.…”

“…For example, both HCA and PAH can induce or promote pancreatic tumors in animals (25,26,34,35). High level of HCA-induced DNA adducts have been detected in pancreatic tissues from animals exposed to HCA (32,33) and from individuals with unknown exposure to HCA (37).…”

“…Animal studies have shown that dietary intake of BaP causes increased levels of tumors at several sites, particularly in the gastrointestinal tract (24). Another PAH compound, dimethylbenzanthracene, has been shown to induce pancreatic ductal adenocarcinomas in rats, and the tumors are histologically similar to those seen in humans (25,26). Epidemiologic studies have associated dietary exposure to HCA and PAH with increased risk for cancers of the colon, breast, prostate, and pancreas (27)(28)(29)(30)(31).…”

Dietary Intake of Heterocyclic Amines and Benzo(a)Pyrene: Associations with Pancreatic Cancer

“…Two other HCAs, 3-amino-1,4-dimethyl-5H-pyriod [4,3-b]indole (Trp-P-1) and 2-amino-3,4,8-trimethylimidazo [4,5-f]quinoxaline (DiMeQx), have shown tumor-promoting activity in hamsters (12). The PAH, dimethylbenzanthracene, when implanted in rats, induces pancreatic ductal adenocarcinomas that are histologically similar to those seen in humans (13,14).…”

Epigenetics and Pancreatic Cancer: The Role of Nutrigenomics

“…Mutated KRAS has high mutation prevalence in pancreatic cancer, reaching as much as 100% in advanced stages of the disease (65,66). However, dietary agents such as high fat diets have been shown to increase KRAS expression (67)(68)(69), while other studies have shown decreased expression with caloric restriction (70,71) and intake of bioactive components found in some vegetables and fruits (72)(73)(74)(75). Using global genomic screening, 12 altered core signaling pathways due to mutations have been found in pancreatic cancer (76).…”