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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1997 Mar;88(3):238–244. doi: 10.1111/j.1349-7006.1997.tb00373.x

Dose‐dependent Induction of Both Pepsinogen‐altered Pyloric Glands and Adenocarcinomas in the Glandular Stomach of C3H Mice Treated with N‐Methyl‐N‐nitrosourea

Masami Yamamoto 1, Chie Furihata 2, Yasunobu Fujimitsu 1, Toshio Imai 1, Ken‐ichi Inada 1, Hayao Nakanishi 1, Masae Tatematsu 1
PMCID: PMC5921371  PMID: 9140107

Abstract

The dose‐response relation for the appearance of pepsinogen isozyme 1 (Pg l)‐altered pyloric glands (PAPG) and the related induction of adenocarcinomas were examined in male C3H mice given N‐methyl‐N‐nitrosourea (MNU) in their drinking water at the concentration of 120 ppm (group 1), 60 ppm (group 2), 30 ppm (group 3) or 0 ppm (group 4) for 30 weeks and then normal tap water. Animals were killed at weeks 10, 30 and 42. Adenomatous hyperplasias and adenocarcinomas were noted from week 30 and their induction was dose‐dependent at week 42. Almost all cells of pyloric gland cell type in those lesions had little or no immunohistochemically demonstratable Pg 1 content, as was also the case for the cells in PAPG, whose numbers per 100 normal‐appearing pyloric glands were found to be MNU dose‐dependent at all experimental time points. The numbers of PAPG at week 10 significantly correlated with the incidences of adenomatous hyperplasias and adenocarcinomas at week 42. Investigation of proliferation by immunohistochemical detection of bromodeoxyuridine (BrdU) labeling in the PAPG at week 10 demonstrated elevation (P <0.05) as compared to normal pyloric glands. Intestinal metaplasia was not a feature in the present experiment and the results suggest that in mice, PAPG might be a preneoplastic lesion involved in gastric chemical carcinogenesis.

Keywords: Preneoplasic lesion, N‐Methyl‐N‐nitrosourea, Pepsinogen 1‐altered pyloric gland, Stomach cancer, Mouse

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REFERENCES

  • 1. ) Sugimura , T. and Fujimura , S.Tumor production in glandular stomach of rats by N‐methyl‐N'‐nitro‐N‐nitro‐soguanidine . Nature , 216 , 943 – 944 ( 1967. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Fujimura , S. , Kogure , K. , Oboshi , S. and Sugimura , T.Production of tumors in glandular stomach of hamsters by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Cancer Res. , 30 , 1444 – 1448 ( 1970. ). [PubMed] [Google Scholar]
  • 3. ) Fox , J. G. , Wishnok , J. S. , Murphy , J. C. , Tannenbaum , S. R. and Correa , P.MNNG‐induced gastric carcinoma in ferrets infected with Helicobacter mustelae . Carcinogenesis , 14 , 1957 – 1961 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Sugimura , T. , Tanaka , N. , Kawachi , T. , Kogure , K. , Fujimura , S. and Shimosato , Y.Production of stomach cancer in dogs by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Gann , 62 , 67 ( 1971. . [PubMed] [Google Scholar]
  • 5. ) Furihata , C. , Iwasaki , Y. , Sugimura , T. , Tatematsu , M. and Takahashi , M.Differentiation of pepsinogen producing cells in the fundic and pyloric mucosa of developing rats . Cell Differ. , 2 , 179 – 189 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Furihata , C. , Saito , D. , Fujiki , H. , Kanai , Y. , Matsushima , T. and Sugimura , T.Purification and characterization of pepsinogens and a unique pepsin from rat stomach . Eur. J. Biockem. , 105 , 43 – 50 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Furihata , C. , Sakajima , K. , Kazama , S. , Kogure , T. , Kawachi , T. , Sugimura , T. , Tatematsu , M. and Takahashi , M.Changes in pepsinogen isozymes in stomach carcinogenesis induced in rats by N‐methyl‐N'‐nitro‐N‐nitrosogu‐anidine . J. Natl. Cancer Inst. , 55 , 925 – 930 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Tatematsu , M. , Saito , D. , Furihata , C. , Miyata , Y. , Nakatsuka , T. , Ito , N. and Sugimura , T.Initial DNA damage and heritable permanent change in pepsinogen isozyme pattern in the pyloric mucosa of rats after short‐term administration of N‐methyl‐N'‐nitro‐N‐nitrosoguani‐dine . J. Natl. Cancer Inst , 64 , 775 – 781 ( 1980. ). [PubMed] [Google Scholar]
  • 9. ) Furihata , C. , Kodama , K. and Matsushima , T.Induction of changes in the pepsinogen content and the pepsinogen isozyme pattern of the pyloric mucosa of the rat stomach by short‐term administration of stomach carcinogens . J. Natl. Cancer Inst. , 67 , 1101 – 1104 ( 1981. ). [PubMed] [Google Scholar]
  • 10. ) Tatematsu , M. , Furihata , C. , Hirose , M. , Shirai , T. , Ito , N. , Nakajima , Y. and Sugimura , Y.Changes in pepsinogen isozymes in stomach cancer induced in Wistar rats by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine and in transplant‐able gastric carcinoma(SG2B) . J. Natl. Cancer Inst. , 58 , 1709 – 1716 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Tatematsu , M. , Furihata , C. , Katsuyama , T. , Mera , Y. , Inoue , T. , Matsushima , T. and Ito , N.Immunohistochem‐ical demonstration of pyloric gland‐type cells with low‐pepsinogen isozyme1 in preneoplastic and neoplastic tissues of rat stomachs treated with N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . J.Natl.Cancer Inst. , 78 , 771 – 777 ( 1987. ). [PubMed] [Google Scholar]
  • 12. ) Tatematsu , M. , Furihata , C. , Mera , Y. , Shirai , T. , Matsushima , T. and Ito , N.Immunohistochemical demonstrationofinductionof pyloricglandswithlow pepsinogen l(Pg 1) content in rat stomach by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Jpn. J. Cancer Res. (Gann) , 77 , 238 – 243 ( 1986. ). [PubMed] [Google Scholar]
  • 13. ) Koike , K. , Hinrichs , S. H. , Isselbacher , K. J. and Jay , G.Transgenic mouse model for human gastric carcinoma . Proc. Natl Acad. Sci. USA , 86 , 5615 – 5619 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Mori , K.Carcinoma of the glandular stomach of mice by instillation of 4‐nitroquinoline 1‐oxide . Gann , 58 , 389 – 393 ( 1967. ). [PubMed] [Google Scholar]
  • 15. ) Mori , K. , Ohta , A. , Murakami , T. , Tamura , M. and Kondo , M.Carcinoma of the glandular stomach of mice induced by 4‐hydroxyaminoquinoline 1‐oxide hydrochlo‐ride . Gann , 60 , 151 – 154 ( 1969. ). [PubMed] [Google Scholar]
  • 16. ) Sugimura , T. and Kawachi , T.Experimental stomach cancer . Methods Cancer Res. , 7 , 245 – 308 ( 1973. ). [Google Scholar]
  • 17. ) Tateraatsu , M. , Ogawa , K. , Hoshiya , T. , Shichino , Y. , Kato , T. , Imaida , K. and Ito , N.Induction of adenocarcinomas in the glandular stomach of BALB/c mice treated with N‐methyl‐N‐nitrosourea . Jpn. J. Cancer Res. , 83 , 915 – 918 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Tatematsu , M. , Yamamoto , M. , Iwata , H. , Fukami , H. , Yuasa , H. , Tezuka , N. , Masui , T. and Nakanishi , H.Induction of glandular stomach cancers in C3H mice treated withN‐methyl‐N‐nitrosourea inthe drinking water . Jpn. J. Cancer Res. , 84 , 1258 – 1264 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Bosman , F.T. , Lindeman , J. , Kuipers , G. , van der Wai , A. , Kreuning , J.The influence of fixation on immunoperoxidase staining of plasma cells in paraffin sections of intestinal biopsy specimens . Histochemistry , 53 , 57 – 62 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Ouchterlony , O.Antigen‐antibody reactions in gels . Acta Pathol. Microbiol. Scand. , 32 , 231 – 240 ( 1953. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Tatematsu , M. , Katsuyama , T. , Fukushima , S. , Takahashi , M. , Shirai , T. , Ito , N. and Nasu , T.Mucin histochemistry by paradoxical concanavalin A staining in experimental gastric cancers induced in Wistar rats by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine or 4‐nitroquinoline 1‐oxide . J, Natl Cancer Inst. , 64 , 835 – 843 ( 1980. ). [PubMed] [Google Scholar]
  • 22. ) Kataoka , K. , Takeoka , Y. and Furihata , C.Immunocytochemical study of pepsinogen 1‐producing cells in the fundic mucosa of the stomach in developing mice . Cell Tissue Res. , 261 , 211 – 217 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Wilson , N. W. , Macartney , J. C.A comparison of in vitro and in vivo gastric mucosal cell kinetics . Lab. Invest. , 58 , 459 – 465 ( 1988. ). [PubMed] [Google Scholar]
  • 24. ) Tatematsu , M. , Mutai , M. , Aoki , T. , de Camargo , J. L. , Furihata , C. and Ito , N.Proliferation kinetics of pepsinogen altered pyloric gland cells in rats treated with N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Carcinogenesis , 10 , 907 – 911 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Tatematsu , M. , Aoki , T. , Inoue , T. , Mutai , M. , Furihata , C , and Ito , N.Coefficient induction of pepsinogen 1‐decreased pyloric glands and gastric cancers in five different strains of rats treated with N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Carcinogenesis , 9 , 495 – 498 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Tamano , S. , Jakubczak , J. , Takagi , H. , Merlino , G. and Ward , J. M.Increased susceptibility to N‐nitrosomethyl‐urea gastric Carcinogenesis in transforming growth factor α transgenic mice with gastric hyperplasia . Jpn. J. Cancer Res. , 86 , 435 – 443 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. ) Sugimura , T. , Fujimura , S. and Baba , T.Tumor production in the glandular stomach and alimentary tract of the rat by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Cancer Res. , 30 , 455 – 465 ( 1970. ). [PubMed] [Google Scholar]
  • 28. ) Saito , T. , Inokuchi , K. , Takayama , S. and Sugimura , T.Sequential morphological changes in N‐methyl‐N'‐nitro‐N‐nitrosoguanidine Carcinogenesis in the glandular stomach of rats . J. Natl. Cancer Inst. , 44 , 769 – 783 ( 1970. ). [PubMed] [Google Scholar]
  • 29. ) Hirota , N. , Aonuma , T. , Yamada , S. , Kawai , T. , Saito , K. and Yokoyama , T.Selective induction of glandular stomach carcinoma in F344 rats by N‐methyl‐N‐nitrosourea . Jpn. J. Cancer Res. (Gann) , 78 , 634 – 638 ( 1987. ). [PubMed] [Google Scholar]
  • 30. ) Ming , S. C. , Goldman , H. and Freima , D. G.Intestinal metaplasia and histogenesis of carcinoma in human stomach. Light and electron microscopic study . Cancer , 20 , 1418 – 1429 ( 1967. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Tatematsu , M. , Furihata , C. , Katsuyama , T. , Hasegawa , R. , Nakanowatari , J. , Saito , D. , Takahashi , M. , Matsushima , T. and Ito , N.Independent induction of intestinal metaplasia and gastric cancer in rats treated with N‐raethyl‐N'‐nitro‐N‐nitrosoguanidine . Cancer Res. , 43 , 1335 – 1341 ( 1983. ). [PubMed] [Google Scholar]

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