Gastric carcinogenesis by N‐Methyl‐N‐Nitrosourea is enhanced in db/db diabetic mice

Abstract

In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia. (Cancer Sci 2009; 100: 1180-1185) A s in almost all countries in the world, type 2 diabetes mellitus (DM) has become a serious public health problem in Japan. Associations between DM and malignant neoplasms have been discussed for many years and several prospective cohort and case-control studies have provided evidence of positive links.(1-4) Recently, a Japanese prospective study showed high hazard ratios for cancers of the liver, pancreas, kidney, colon, ovaries and stomach. The Japanese population is characterized by a high morbidity from gastric cancer. In a prospective epidemiological study about gastric cancer and DM, described in 2005, Yamagata et al. surveyed 2466 cases, and concluded a modest increase in fasting plasma glucose levels to be a risk factor for gastric cancer among Helicobacter pylori-seropositive subjects.(6) Furthermore, insulin can stimulate insulin-like growth factor 1 receptor (IGF-1R), (7) and leptin induces gastric cancer cell proliferation, (8,9) while adiponectin inhibits the growth and peritoneal metastasis of gastric cancer.(10) However, corroboratory experimental evidence is limited and no animal model has hitherto shown any association between DM and gastric cancer. In the present study we investigated whether hyperglycemia and/or hyperinsulinemia are risk factors for gastric cancer using genetically predisposed diabetic (db/db) mice treated with N-methyl-N-nitrosourea (MNU), a carcinogen well established to induce adenocarcinomas in...

Effects of IGF2BP2, KCNQ1 and GCKR Polymorphisms on Clinical Outcome in Metastatic Gastric Cancer Treated with EOF Regimen

“…An animal model of diabetes was more susceptible to chemical induction of gastric carcinogenesis [9]. The pooled results of 20 published studies supported a positive association between diabetes and the risk of GC, and supported the notion that diabetes was significantly associated with mortality in patients with GC [10].…”

Prospective Study of Self-Reported Diabetes and Risk of Upper Gastrointestinal Cancers

“…The mechanistic link between diabetes and gastric cancer has been explored in diabetic mice, which have been shown to be more susceptible to chemical induction of gastric carcinogenesis (26). Inflammation has been implicated as an important etiologic factor in both insulin resistance and Type 2 diabetes (27), and chronic inflammation also plays a role in the development of gastric atrophy and cancer (28).…”

Special Licorice Extracts Containing Lowered Glycyrrhizin and Enhanced Licochalcone A Prevented Helicobacter pylori‐Initiated, Salt Diet‐Promoted Gastric Tumorigenesis

“…All animal studies were carried out in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of CHA University CHA Cancer Institute after IRB approval. Two hours before necropsy, 200 mg/kg of body weight of bromodeoxyuridine (5‐bromo‐2′‐deoxyuridine, BrdU, ≥99% HPLC, sigma) in saline was injected to mice by intraperitoneally . Stomachs were isolated and subjected to a histologic examination, ELISA, Western blotting, and RT‐PCR.…”