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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1995 May;86(5):435–443. doi: 10.1111/j.1349-7006.1995.tb03076.x

Increased Susceptibility to N‐Nitrosomethylurea Gastric Carcinogenesis in Transforming Growth Factor α Transgenic Mice with Gastric Hyperplasia

Seiko Tamano 1,†, John Jakubczak 2, Hitoshi Takagi 2,‡, Glenn Merlino 2, Jerrold M Ward 1,✉
PMCID: PMC5920850  PMID: 7790317

Abstract

Glandular stomach carcinogenesis after N‐nitrosomethylurea (NMU) treatment was examined in transgenic mice bearing a human transforming growth factor alpha (TGF‐α) cDNA driven by the mouse metallothionein‐I promoter (mouse line MT100) in the inbred mouse line FVB/N. Untreated MT100 mice exhibit a severe age‐related gastric fundic hyperplasia. Both sexes of MT100 mice were given 10 weekly intragastric intubations of 0.5 mg NMU per mouse from 6 weeks of age and/or zinc chloride in drinking water to stimulate transgene expression from 5.5 weeks of age to the experiment termination. Animals were killed sequentially at 10, 19 and 29 experimental weeks. Several histochemical markers (AB‐PAS, TGF‐α, pepsinogen isozyme 1, proliferating cell nuclear antigen) were used. Abnormal histochemical patterns were found in untreated MT100 and NMU‐treated MT100 mice for all 4 markers of differentiation and carcinogenesis. Precancerous lesions including atypical and/or adenomatous hyperplasia were found in the fundic region of 16/22 male and 8/22 female MT100 mice but not in 27 male and 24 female FVB/N mice treated with NMU. One of 22 MT100 males had fundic carcinoma. FVB/N mice treated with NMU had neither precancerous lesions nor carcinomas in the fundus. Well differentiated adenocarcinomas in the pyloric region were induced at incidences of 2/22 male and 1/22 female MT100 mice treated with NMU and 4/27 male and 4/24 female FVB/N mice treated with NMU. Both strains also had a high incidence (55 to 92%) of squamous cell carcinomas of the forestomach. In conclusion, TGF‐α induced a hyperplastic lesion in the gastric fundus that appeared to predispose the MT100 mice to carcinogenesis by NMU.

Keywords: N‐Nitrosomethylurea, Glandular stomach carcinoma, Transgenic mouse, Transforming growth factor α

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REFERENCES

  • 1).Fowlis , D. J. and Balmain , A.Oncogenes and tumour suppressor genes in transgenic mouse models of neoplasia . Eur. J. Cancer , 29A , 638 – 645 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 2).Merlino , G.Transgenic mice as models for tumorigenesis . Cancer Invest. , 12 , 203 – 213 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 3).Jhappan , C. , Stahle , C. , Harkins , R. N. , Fausto , N. , Smith , G. H. and Merlino , G. T.TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas . Cell , 61 , 1137 – 1146 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 4).Sandgren , E. P. , Luetteke , N. C. , Palmiter , R. D. , Brinster , R. L. and Lee , D. C.Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast . Cell , 61 , 1121 – 1135 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 5).Matsui , Y. , Halter , S. A. , Holt , J. T. , Hogan , B. L. M. and Coffey , R. J. , Jr.Development of mammary hyperplasia and neoplasia in MMTV‐TGF‐α transgenic mice . Cell , 61 , 1147 – 1155 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 6).Vassar , R. and Fuchs , E.Transgenic mice provide new insights into the role of TGF‐α during epidermal development and differentiation . Genes Dev. , 5 , 714 – 727 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 7).Lee , L. W. , Raymond , V. W. , Tsao , M.‐S. , Lee , D. C. , Earp , H. S. and Grisham , J. W.Clonal cosegregation of tumorigenicity with overexpression of c‐myc and transforming growth factor α genes in chemically transformed rat liver epithelial cells . Cancer Res. , 51 , 5238 – 5244 ( 1991. ). [PubMed] [Google Scholar]
  • 8).Takagi , H. , Sharp , R. , Hammermeister , C. , Goodrow , T. , Bradley , M. O. , Fausto , N. and Merlino , G.Molecular and genetic analysis of liver oncogenesis in transforming growth factor α transgenic mice . Cancer Res. , 52 , 5171 – 5177 ( 1992. ). [PubMed] [Google Scholar]
  • 9).Murakami , H. , Sanderson , N. D. , Nagy , P. , Marino , P. A. , Merlino , G. and Thorgeirsson , S. S.Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c‐myc and transforming growth factor α in hepatic oncogenesis . Cancer Res. , 53 , 1719 – 1723 ( 1993. ). [PubMed] [Google Scholar]
  • 10).Sandgren , E. P. , Luetteke , N. C. , Qiu , T. H. , Palmiter , R. D. , Brinster , R. L. and Lee , D. C.Transforming growth factor alpha dramatically enhances oncogene‐induced carcinogenesis in transgenic mouse pancreas and liver . Mol. Cell. Biol. , 13 , 320 – 330 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11).Takagi , H. , Sharp , R. , Takayama , H. , Anver , M. R. , Ward , J. M. and Merlino , G.Collaboration between growth factors and diverse chemical carcinogens in hepatocarcinogenesis of transforming growth factor α transgenic mice . Cancer Res. , 53 , 4329 – 4336 ( 1993. ). [PubMed] [Google Scholar]
  • 12).Coffey , R. J. , Jr. , Meise , K. S. , Matsui , Y. , Hogan , B. L. M. , Dempsy , P. J. and Halter , S. A.Acceleration of mammary neoplasia in transforming growth factor α transgenic mice by 7,12‐dimethylbenzanthracene . Cancer Res. , 54 , 1678 – 1683 ( 1994. ). [PubMed] [Google Scholar]
  • 13).Tamano , S. , Merlino , G. T. and Ward , J. M.Rapid development of hepatic tumors in transforming growth factor α transgenic mice associated with increased cell proliferation in precancerous hepatocellular lesions initiated by N‐nitrosodiethylamine and promoted by phenobarbital . Carcinogenesis , 15 , 1791 – 1798 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 14).Takagi , H. , Jhappan , C. , Sharp , R. and Merlino , G.Hypertrophic gastropathy resembling Meneterier's disease in transgenic mice overexpressing transforming growth factor α in the stomach . J. Clin. Invest. , 90 , 1161 – 1167 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15).Sharp , R. , Babyatsky , M. , Takagi , H. , Tågerud , S. , Wang , T. C. , Bockman , D. E. , Brand , S. J. and Merlino , G.Transforming growth factor‐α disrupts the normal program of cellular differentiation in the gastric mucosa of transgenic mice . Development , 121 , 149 – 161 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 16).Furihata , C. , Kawachi , T. and Sugimura , T.Premature induction of pepsinogen in developing rat gastric mucosa by hormones . Biochem. Biophys. Res. Commun. , 47 , 705 – 711 ( 1972. ). [DOI] [PubMed] [Google Scholar]
  • 17).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. Biochem. , 105 , 43 – 50 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 18).Furihata , C. , Sasajima , 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‐nitrosoguanidine . J. Natl. Cancer Inst. , 55 , 925 – 930 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 19).Tatematsu , M. , Furihata , C , Mera , Y. , Shirai , T. , Matsushima , T. and Ito , N.Immunohistochemical demonstration of induction of pyloric glands with low pepsinogen 1 (Pg 1) content in rat stomach by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine . Jpn. J. Cancer Res. , 77 , 238 – 243 ( 1986. ). [PubMed] [Google Scholar]
  • 20).Tatematsu , M. , Furihata , C. , Katsuyama , T. , Mera , Y. , Inoue , T. , Matsushima , T. and Ito , N.Immunohistochemical demonstration of pyloric gland‐type cells with lowpepsinogen isozyme 1 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]
  • 21).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]
  • 22).Kataoka , K. , Takeoka , Y. and Furihata , C.Immuno‐cytochemical 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).Tatematsu , 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]
  • 24).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 with N‐methyl‐N‐nitrosourea in the drinking water . Jpn. J. Cancer Res. , 84 , 1258 – 1264 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25).Sugimura , T. and Kawachi , T.Experimental stomach cancer . Methods Cancer Res. , 7 , 245 – 308 ( 1973. ). [Google Scholar]
  • 26).Lee , G.‐H. , Merlino , G. and Fausto , N.Development of liver tumors in transforming growth factor α‐transgenic mice . Cancer Res. , 52 , 5162 – 5170 ( 1992. ). [PubMed] [Google Scholar]
  • 27).Thomas , D. G. , Breslow , N. and Gart , J. J.Trend and homogeneity analyses of proportions and life table data . Comput. Biomed. Res. , 10 , 373 – 381 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 28).Bockman , D. , Sharp , R. and Merlino , G.Regulation of terminal differentiation of zymogenic cells by transforming growth factor alpha in transgenic mice . Gastroenterology , 108 , 447 – 454 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 29).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]
  • 30).Strayer , D. S. , Shijun , Y. and Schwartz , M. S.Epidermal growth factor‐like growth factors. I. Breast malignancies and other epithelial proliferations in transgenic mice . Lab. Invest. , 69 , 660 – 673 ( 1993. ). [PubMed] [Google Scholar]
  • 31).Yoshida , K. , Kyo , E. , Tsujino , T. , Sano , T. , Niimoto , M. and Tahara , E.Expression of epidermal growth factor, transforming growth factor‐α and their receptor genes in human gastric carcinomas; implication for autocrine growth . Jpn. J. Cancer Res. , 81 , 43 – 51 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32).Yasui , W. , Ji , Z.‐Q. , Kuniyasu , H. , Ayhan , A. , Yokozaki , H. , Ito , H. and Tahara , E.Expression of transforming growth factor alpha in human tissues: immunohistochemical study and Northern blot analysis . Virchows Arch. A Pathol. Anat. , 421 , 513 – 519 ( 1992. ). [DOI] [PubMed] [Google Scholar]

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