Incidence Of Gastric Tumors Research Articles

Avicennia alba mangrove derived squalene compound inhibited the MNNG induced gastric cancer in Albino rats

ABSTRACTThe chemo-preventive effects of Squalene compound from Avicennia alba leaves on N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis (intragastrically) in albino rats were analyzed. The animals were divided into four groups with six animals in each group. Group 1 was the control, Group 2 was administrated 150mg bw−1 MNNG for two times at 3-week interval. Group 3 was given MNNG and Squalene 50µg bw−1 and group 4 was given only Squalene at the end of the experiment (25 weeks). Squalene prolonged the survival of MNNG-induced cancer bearing animals and delayed the onset of tumor in animals administrated with Squalene and MNNG simultaneously. The incidence of gastric tumors in group 2 was 91.5% (5/6 animals) with a mean tumor burden of 117.14mm3. The lipid peroxidation in the stomach tumor tissue was associated with enhanced antioxidant levels. The level of antioxidant effects increased in Squalene group, while it decreased in MNNG groups. Data suggested that Squalene from A. alba extract may have a beneficial effect on patients with gastric cancer.

Effect of N-Methyl-N-Nitrosourea on Helicobacter-induced Gastric Carcinogenesis in C57BL/6 Mice.

BackgroundThe aim of this study was to investigate the effect of N-methyl-N-nitrosourea (MNU) treatment followed by chronic Helicobacter pylori SS1 and H. felis colonization on the stomachs of C57BL/6 mice. The role of MNU and Helicobacter species in gastric carcinogenesis was also elucidated.MethodsA total of 69 C57BL/6 mice at 4 weeks of age were divided into 6 groups according to MNU treatment and H. pylori SS1 or H. felis infection. The mice were sacrificed at 21 and 50 weeks. The degree of inflammation was determined by histopathology. The levels of gastric mucosal myeloperoxidase, TNF-α, and interleukin-1β (IL-1β) were measured by ELISA.ResultsIn the H. felis groups with or without MNU, the incidence of gastric tumors was 21.1% and 35.0% at 21 and 50 weeks, respectively. No gastric tumors were observed in all control mice. At 50 weeks, 37.5% of gastric adenoma cases were observed in the H. felis alone and MNU + H. felis groups. Furthermore, 12.5% of gastric adenocarcinoma cases were observed in the MNU alone and MNU + H. felis groups. The gastric mucosal IL-1β level was significantly higher in the MNU + H. felis group at 21 weeks and H. felis group at 50 weeks, respectively, than that for control mice (P < 0.05). However, the effect of MNU on H. pylori SS1-induced gastric carcinogenesis was low compared to that on H. felis.ConclusionsAdministration of MNU before H. felis infection provokes severe inflammation through IL-1β, and eventually induces gastric cancer. However, the role of MNU in H. pylori SS1-induced gastric carcinogenesis model is minor.

Ablation of osteopontin suppresses N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric cancer development in mice.

Several clinical studies have reported increased expression of osteopontin (OPN) in various types of human cancer, including gastric cancer. However, the precise mechanisms underlying tumor development remain unclear. In the present study, we investigated the pathogenic roles of OPN in Helicobacter pylori-induced gastric cancer development. Wild-type (WT) and OPN knockout (KO) mice were treated with N-methyl-N-nitrosourea (MNU) and infected with H.pylori. Mice were killed 50 weeks after treatment, and stomach tissues were assessed by histopathological examination, immunohistochemistry, quantitative real-time RT-PCR and western blotting. To clarify the carcinogenic effects of OPN, we also conducted an in vitro study using AGS human gastric cancer cell line and THP-1 human monocytic cell line. The overall incidence of gastric tumors was significantly decreased in OPN KO mice compared with WT mice. Apoptotic cell death was significantly enhanced in OPN KO mice and was accompanied by upregulation of signal transducer and activator of transcription 1 (STAT1) and inducible nitric oxide synthase (iNOS). In vitro study, OPN suppression also caused STAT1 upregulation and iNOS overexpression in AGS and THP-1 cells, which resulted in apoptosis of AGS cells. In addition, a negative correlation was clearly identified between expression of OPN and iNOS in human gastric cancer tissues. Our data demonstrate that loss of OPN decreases H.pylori-induced gastric carcinogenesis by suppressing proinflammatory immune response and augmenting STAT1 and iNOS-mediated apoptosis of gastric epithelial cells. An important implication of these findings is that OPN actually contributes to the development of gastric cancer.

Chemopreventive effects of garlic and mugwort mixture extract on Helicobacter pylori-associated mouse gastric carcinogenesis

Garlic and mugwort have long been used in traditional medicine to prevent various diseases. Several in vitro studies have reported protective efficacies of garlic and mugwort in cases of gastric cancer. In the present study, we investigated the cancer preventive effects of garlic and mugwort mixture extract (GME) in a Helicobacter (H.) pylori-associated gastric carcinogenesis mouse model. To induce gastric cancer, C57BL/6 mice were treated with N-methyl-N-nitrosourea and H. pylori. Various concentrations of GME (0, 100, 500, and 1,000 ppm) were then fed to the mice for 38 weeks, after which the tumor tissues were examined for histopathology, mucin histochemistry and -catenin. The incidence of gastric tumors was significantly lower in the highest dose GME-treated mice (46.7%) than control mice (85.7%) (p

Chemopreventive effects of elm tree bark extract onHelicobacter pylori‐associated mouse gastric carcinogenesis

ABSTRACTBackground and aim:Extracts of elm tree (Ulmus davidiana japonica) have long been used for the treatment of inflammatory diseases in traditional medicine. Severalin vitrostudies have indicated that some components of the elm tree have anti‐inflammatory and/or anti‐oxidative effects. We investigated the chemopreventive effects of bark extract of elm tree (BEE) on a chronic inflammation‐associated mouse gastric cancer model.Methods:Gastric cancer was generated by the combination treatment ofN‐methyl‐N‐nitrosourea andHelicobacter pylorito C57BL/6 mice. Various concentrations of BEE (0, 125, 250, 500, and 1,000 ppm) was fed to the mice for 38 weeks.Results:The incidence of gastric tumors at 50 weeks were significantly lower in the highest dose BEE‐fed mice (26.67%) than control mice (85.71%) (P &lt; 0.01). The multiplicity and size of tumors were also significantly lowered by BEE feeding in a dose‐dependent manner (P &lt; 0.01). In addition, BEE decreased the nuclear β‐catenin localization and nuclear cyclin‐D1 expression in adenocarcinomas. Furthermore, BEE suppressedH. pylori‐associated chronic inflammation determined by histologic gradings ofH. pyloridensity, chronic gastritis, glandular atrophy and intestinal metaplasia in non‐tumorous gastric mucosae.Conclusions:These findings suggest that BEE inhibits the development of gastric tumorigenesis via suppression ofH. pyloriinfection‐associated chronic inflammation.

Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers and mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this article, we review the data on the susceptibility of p53 nullizygote (-/-), heterozygote (+/-), and wild type (+/+) mice to various carcinogens. Induction of esophageal and tongue squamous cell carcinomas (SCCs) by methyl-n-amylnitrosamine was shown to be increased in p53 (+/-) mice, in addition to the high sensitivity shown by p53 (-/-) littermates. N,N-dibutylnitrosamine (DBN) treatment also caused more tumor development in p53 (+/-) than wild-type mice, as with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the urinary bladder. In addition, p53 (+/-) heterozygotes proved more sensitive than wild type littermates to the induction of stromal cell tumors like hemangiomas/hemangiosarcomas by N-bis(2-hydroxypropyl)nitrosamine (BHP) or lymphomas and fibrosarcomas with other carcinogens. Analysis of exons 5-8 of the p53 gene demonstrated mutations in approximately one half of the lesions. With N-methyl-N-nitrosourea, preneoplastic lesions of the stomach, pepsinogen altered pyloric glands (PAPG), and a gastric adenocarcinoma, were found after only 15 weeks in p53 (-/-) mice, although there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice in the longer-term. Regarding colon carcinogenicity, adenocarcinomas were observed limited to 1, 2-dimethylhydrazine treated p53 (-/-) mice in the short term, but again, no significant difference was evident between the p53 (+/+) and (+/-) cases at the end of the study. Furthermore, diethylnitrosamine or aminophenylnorharman treated p53 (+/-) mice did not demonstrate elevated susceptibility to tumors in the liver. With BHP, which induces tumors in multiple organs, p53 (+/-) mice were not more statistically sensitive with regard to lung tumor development than p53 (+/+). Of the malignant tumors examined in p53 (+/+) and (+/-) mice, as many as 10% demonstrated mutations in the p53 gene. These results suggest that p53 may not be a direct target for mouse adenomas/adenocarcinomas, but rather plays an important role as a gatekeeper in their genesis. In contrast p53 itself is frequently mutated in squamous, urothelial, or stromal tumors with a clear order of susceptibility: p53 (-/-) > p53 (+/-) > p53 (+/+) mice. p53 (-/-) mice are versatile animals for carcinogenicity testing, despite their disadvantage of a high background of spontaneous tumor development, and tissue dependence must be taken into account when exposing p53 (+/-) mice to chemical carcinogens.

No susceptibility of colon tissue implanted into the glandular stomach of rats to N-nitroso-N-methylurea carcinogenesis.

The present study was undertaken to determine the response of colonic mucosa implanted into the stomach fundus in 6-week-old male F344 rats to oral administration of N-nitroso-N-methylurea (MNU). In graft + MNU, 15% animals had tumors in the implanted colon tissue whereas a 26% incidence of gastric tumors was observed for the pyloric mucosa. In MNU alone, 30% of rats demonstrated gastric tumors. In graft alone 10% of tumors were observed in the grafted site but none in the pylorus. Thus while graft tissue may intrinsically have an elevated risk of tumor development, no susceptibility to MNU was observed in the present study.

Colon tissue implanted into the glandular stomach in rats lack susceptibility to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) carcinogenesis

The present study was undertaken to determine the response of colon mucosa implanted into the fundus of stomach in 6-week old male F344 rats to oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Samples of colonic tissue about 8 mm in diameter were obtained from various colon sites and surgically implanted into the anterior wall of the fundus by isografting. MNNG was chronically administered at a concentration of 100 mg/l in the drinking water for 16 weeks starting 4 weeks after the operation and the grafted colon mucosa was examined at 12 months after the operation. Control rats received a sham-operation and the same amount of MNNG. In the MNNG administered groups, only one adenoma containing Paneth cells was noted in the implanted colon tissue whereas over 40% incidence of gastric tumors was observed in the pyloric mucosa. In the operated rats not given MNNG no gastric tumors were observed in either the grafted site or the pylorus.

Progesterone enhancement of stomach tumor development in SD rats treated with N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of chronic progesterone treatment on gastric tumorigenesis were examined in 6‐week‐old male SD rats. The rats were castrated, progesterone or testosterone pellets were implanted, and, starting one week after the operation, 100 mg/liter of N‐methyl‐N‐nitro‐N'‐nitrosoguanidine (MNNG) was administered in the drinking water for 16 weeks. Every 2 months the pellets were changed. Group 1 animals received castration plus MNNG while Groups 2 and 3 also received progesterone and testosterone, respectively. In the Group 4 case, progesterone and testosterone were administered alternately for 2‐month periods and in Group 5 MNNG was given to intact animals. All survivors were killed one year after the start of MNNG treatment. In Group 1 the incidence of gastric tumors was significantly decreased as compared with the Group 5 value. The Group 2 incidence, in contrast, was similar to that in Group 5, and the size of the observed gastric tumors was massively increased. The area of the pyloric gland mucosa was also greater than in other groups. Testosterone treatment was associated with a less pronounced increase in tumor size and a recovery in incidence. The results indicate that progesterone may exert a promoting influence on gastric tumor development.

High incidence of other neoplasms in patients with low-grade gastric MALT lymphoma

Low-grade gastric MALT lymphoma is an uncommon tumour for which a close association with chronic Helicobacter pylori infection has been suggested. However, given the rarity of MALT lymphoma of the stomach despite the high prevalence of H. pylori infection, it seems plausible that genetic host factors might play a fundamental role in gastric lymphomagenesis. We retrospectively reviewed the medical records of 83 patients with low-grade gastric MALT, all of whom resided in a geographic area (southern Switzerland and northern Italy) where the incidence of gastric tumours appears to be uncommonly high. One or more additional cancers were observed in 17 of 83 patients (20%, 95% CI 12% to 31%) for a total of 23 tumours. Of these, 5 were diagnosed prior to, 12 concomitantly with, and 7 after the gastric MALT lymphoma. Eleven patients had a single additional solid tumour (13%, 95% CI 7% to 22%); 3 patients had non-Hodgkin's lymphoma and one had Hodgkin's disease. Multiple additional cancers were present in 3 cases. Nine of 83 patients have died and 8 of them of a second cancer. Unexpectedly an extraordinarily large number of patients with other malignancies was observed in this series. The reasons for this finding are still unknown, but genetic alterations are speculated to play an important role.

The effect of sodium chloride and ethanol on x-irradiated gastric mucosa of rats.

Five-week-old JCR: CD rats were administered either with 10% sodium chloride (NaCI) or with 10% ethanol in drinking water after a single dose of 20 Gy of X-irradiation exposed to the gastric region. One year after X-irradiation, the animals were sacrificed. The incidence of gastric tumors was 19% in the X-ray group, 37% in the X-ray plus NaCI, and 10% in the X-ray plus ethanol (X-ray+NaCl vs. X-ray+ethanol p<0.05). The frequency of intestinal metaplasia with alkaline phosphatase (ALP) positive foci in X-ray+NaCl was significantly decreased compared to those of the X-ray or X-ray+ethanol group. The heights of pyloric and fundic mucosa were increased in NaCI groups. It was concluded that 10% NaCI worked as a promotive for the gastric tumorigeneis induced by X-ray but was inhibitory for the appearance of intestinal metaplasia.

Effect of prolactin on gastric tumorigenesis in rats.

The effect of prolactin (PRL) on gastric tumorigenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in 5-week-old F344: JCR rats. A pituitary gland from female rats of same age was implanted into a spleen of male with silicone capsule containing estrone. One month after implantation, 100mg/l of MNNG were given for 6 months. Animals were sacrificed one year after the MNNG administration. The incidence of gastric tumors was 8/31 (26%) and 3/23 (13%) with or without the implantation, respectively. Serum PRL level but not growth hormone was increased in the group implanted with the pituitary gland. There was no correlationship between gastric tumors and level of PRL.

The effect of antioxidants on MNNG-induced stomach carcinogenesis in rats.

The effect of vitamins A, C and E, butylated hydroxytoluene (BHT) and glutathione (GSH) on gastric carcinogenesis induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) was investigated. Male and female BD-VI rats 2-3 months old received a single oral application of MNNG dissolved in corn oil. The male rats were divided into four groups: Group-I: MNNG 250 mg/kg by intubation; Group-II: MNNG + vitamin C daily in the drinking water (400 mg/l); Group-III: MNNG + vitamin C (400 mg/l) + 100 g of milk broth (for each of 10 rats) containing vitamin A (40,000 IU), vitamin E (0.5 g) and BHT (0.1 g) three times a week. The treatment with antioxidants started 7 days before the MNNG administration and continued until the end of experiment. Group-IV rats received MNNG + oxyferriscorbone, i.p. as a single dose of 1.0 mg/kg, daily during the week before and the week after MNNG exposure and than 3 times a week till the end of the experiment. Female rats were divided into two groups: Group-I: MNNG 333 mg/kg by intubation; Group-II: MNNG + GSH orally at a dose of 100 mg/rat 1 h before and 5, 24, 48, and 72 h after MNNG intubation. The incidence of gastric tumors after 15 months of treatment was as follows: male rats, 82.4% in Group-I, 40.0% in Group-II, 40.7% in Group-III, and 50.0% in Group-IV; female rats; 72.7% in Group-I, and 36.0% in Group-II.

Relationship Between Gastric Tumorigenesis and Intestinal Metaplasia in Rats Given X-Radiation and/or &lt;italic&gt;N&lt;/italic&gt;-Methyl-&lt;italic&gt;N′&lt;/italic&gt;-Nitro-&lt;italic&gt;N&lt;/italic&gt;-Nitrosoguanidine&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;

The influence of x-radiation and N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7] on intestinal metaplasia and gastric tumorigenesis was examined in 5-week-old male Crj:CD(SD) rats. The animals were treated either with two 10-Gy fractions of x-rays separated by 3 days for a total of 20 Gy to the gastric region and/or with MNNG orally for 4 months. Simultaneous treatment with x-rays and MNNG (group II) and MNNG only (group IV) induced gastric tumors in the majority of the animals. Sequential treatment with x-radiation and MNNG, either x-ray 2 months prior to MNNG (group I) or MNNG 2 months prior to x-ray (group III), resulted in a lower incidence of gastric tumors as compared with the incidence after treatment with MNNG alone. The frequencies of intestinal metaplasia in the x-irradiated groups (groups I and V) were significantly higher than those in group II, III, or IV. The incidence of intestinal metaplasia and of gastric tumor was inversely proportional. These results indicate that intestinal metaplasia does not play a role in the induction of gastric tumors by MNNG.

Gastric carcinoma developing in chronic gastric ulcer in the rat treated with N-methyl- N1-nitro- N-nitrosoguanidine

The purpose of this experiment was to determine if chronic gastric ulcer in the rat is prediposed to tumor formation when exposed to a known gastric carcinogen. N-methyl- N 1-nitro- N-nitrosoguanidine (NG). Rats were subjected to a standard ulcer-producing operation. Treatment with oral NG (as drinking water) was continued for at least 40 weeks. Appropriate control groups underwent sham operation and/or were fed with tap water. The experiment terminated at 52 weeks. The results showed that significantly more tumors were found at the edge of a chronic ulcer or at the site of previous mucosal injury in the rats which had the ulcer-producing operation and fed with NG than controls ( P < 0.005). However, the number of tumors per rat stomach was the same when the rats were treated with NG whether an ulcer-producing operation or a sham operation was carried out. Furthermore, 18 52 rats in the group with ulcer-producing operation and NG had chronic ulcers without tumors. It is concluded that, in the rat, the presence of a chronic gastric ulcer is more likely to localize the development of a tumor to the ulcer or to the site of previous injury, but does not increase the overall incidence of gastric tumors.