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Carcinogen-induced pancreatic lesions in the mouse: effect of Smad4 and Apc genotypes

Oncogene volume 21, pages 4696–4701 (2002)Cite this article

Abstract

Mutations in the tumour suppressor genes SMAD4 (DPC4, deleted in pancreatic cancer locus 4) and adenomatous polyposis coli (APC) have been implicated in the development of pancreatic cancer in humans. Treatment of wild-type, Smad4+/−, ApcMin/+ or ApcMin/+Smad4+/− mice with N-Nitroso-N-Methyl Urea (NMU) results in abnormal foci in pancreatic acinar cells characterized by increased levels of β-catenin. Previously such foci have been shown to be the precursors of pancreatic neoplasia. Interestingly, only NMU-treated ApcMin/+Smad4+/− mice exhibit a significant increase in abnormal pancreas, which was found to be due to increased number of abnormal foci rather than increased focus size. A range of foci sizes were analysed, but only smaller abnormal foci were characterized by morphological nuclear atypia. These studies suggest functional co-operation between TGF-β and Wnt signalling pathways in the suppression of pancreatic tumorigenesis in the mouse.

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References

  • Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K, Brennan M, Cameron JL, Klimstra DS . 2002 Am. J. Pathol. 160: 953–962

  • Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M . 1988 Cell 53: 549–554

  • Asamura H, Nakajima T, Mukai K, Noguchi M, Shimosato Y . 1989 Cancer 64: 1657–1664

  • Atfi A, Buisine M, Mazars A, Gespach C . 1997 J. Biol. Chem. 272: 24731–24734

  • Barka T . 1982 J. Natl. Cancer Inst. 69: 1115–1120

  • Bottinger EP, Jakubczak JL, Roberts IS, Mumy M, Hemmati P, Bagnall K, Merlino G, Wakefield LM . 1997 EMBO J. 16: 2621–2633

  • Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE . 1994 Nat. Genet. 8: 27–32

  • Clarke AR, Cummings MC, Harrison DJ . 1995 Oncogene 11: 1913–1920

  • Conlon KC, Howe JR . 1997 Surg. Oncol. 6: 1–18

  • Corominas M, Perucho M, Newcomb EW, Pellicer A . 1991 Cancer Res. 51: 5129–5133

  • de Caestecker MP, Piek E, Roberts AB . 2000 J. Natl. Cancer Inst. 92: 1388–1402

  • Diamond LE, Berman JW, Pellicer A . 1987 Cell Immunol. 107: 115–120

  • Gavrieli Y, Sherman Y, Ben-Sasson SA . 1992 J. Cell Biol. 119: 493–501

  • Grau AM, Zhang L, Wang W, Ruan S, Evans DB, Abbruzzese JL, Zhang W, Chiao PJ . 1997 Cancer Res. 57: 3929–3934

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M . 1991 Cell 66: 589–600

  • Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE . 1996a Science 271: 350–353

  • Hahn SA, Hoque AT, Moskaluk CA, da Costa LT, Schutte M, Rozenblum E, Seymour AB, Weinstein CL, Yeo CJ, Hruban RH, Kern SE . 1996b Cancer Res. 56: 490–494

  • Hahn SA, Schmiegel WH . 1998 Digestion 59: 493–501

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da-Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512

  • Heldin CH, Miyazono K, ten Dijke P . 1997 Nature 390: 465–471

  • Keighren M, West JD . 1993 Histochem. J. 25: 30–44

  • Kerr JF, Wyllie AH, Currie AR . 1972 Br. J. Cancer 26: 239–257

  • Kito K, Kihana T, Sugita A, Murao S, Akehi S, Sato M, Tachibana M, Kimura S, Ueda N . 1996 Mol. Carcinog. 17: 78–83

  • Kongkanuntn R, Bubb VJ, Sansom OJ, Wyllie AH, Harrison DJ, Clarke AR . 1999 Oncogene 18: 7219–7225

  • Labbe E, Letamendia A, Attisano L . 2000 Proc. Natl. Acad. Sci. USA 97: 8358–8363

  • Lawrence JB, Singer RH, McNeil JA . 1990 Science 249: 928–932

  • Markowitz SD, Roberts AB . 1996 Cytokine Growth Factor Rev. 7: 93–102

  • Miyaki M, Iijima T, Konishi M, Sakai K, Ishii A, Yasuno M, Hishima T, Koike M, Shitara N, Iwama T, Utsunomiya J, Kuroki T, Mori T . 1999 Oncogene 18: 3098–3103

  • Monis B, Valentich MA, Urrutia R, Rivolta M . 1991 Int. J. Pancreatol. 8: 119–131

  • Moser AR, Pitot HC, Dove WF . 1990 Science 247: 322–324

  • Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P . 1995 Proc. Natl. Acad. Sci. USA 92: 3046–3050

  • Nishita M, Hashimoto MK, Ogata S, Laurent MN, Ueno N, Shibuya H, Cho KW . 2000 Nature 403: 781–785

  • Polakis P . 1997 Biochim. Biophys. Acta 1332: F127–F147

  • Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, Kern SE . 1997 Cancer Res. 57: 1731–1734

  • Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C, Hirohashi S . 1993 Am. J. Pathol. 142: 1534–1543

  • Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RAJ, Meltzer PS, Hahn SA, Kern SE . 1996 Cancer Res. 56: 2527–2530

  • Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE, Rossant J, Mak TW . 1998 Genes Dev. 12: 107–119

  • Sokal RR, Rohlf FJ . 1995 Biometry: The Principles and Practice of Statistics in Biological Research 3rd edn New York: WH Freeman & Co. pp 151 434–439

    Google Scholar 

  • Suzuki K, Hirooka Y, Tsujitani S, Yamane Y, Ikeguchi M, Kaibara N . 2000 Anticancer Res. 20: 1257–1262

  • Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM . 1998 Cell 92: 645–656

  • Takaku K, Miyoshi H, Matsunaga A, Oshima M, Sasaki N, Taketo MM . 1999 Cancer Res. 59: 6113–6117

  • Tetsu O, McCormick F . 1999 Nature 398: 422–426

  • Xu X, Brodie SG, Yang X, Im YH, Parks WT, Chen L, Zhou YX, Weinstein M, Kim SJ, Deng CX . 2000 Oncogene 19: 1868–1874

  • Yang X, Li C, Xu X, Deng C . 1998 Proc. Natl. Acad. Sci. USA 95: 3667–3672

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Acknowledgements

We thank the Staff in the MMTU, Histology Laboratory and Pathology Imaging Suite, K Takaku for assistance with the Smad4 Immunohistochemistry, D Bruce and R James for assistance with DNA-DNA in situ hybridisation. NJ Sphyris, O Sansom, SM Sheahan, M Link and PA Barfoot we thank for helpful discussions. This work was funded by the Cancer Research Campaign (now Cancer Research UK).

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Authors and Affiliations

  1. Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK

    Jan Cullingworth, Martin L Hooper, David J Harrison, Charles E Patek & Alan R Clarke

  2. Section of Biomedical Sciences, Medical School, Teviot Place, Edinburgh, EH8 9AG, UK

    John O Mason

  3. Department of Biomedical Sciences, Cardiff University, Cardiff, CF10 3US, UK

    Alan R Clarke

  4. Brain Tumor Research Center, Montreal Neurological Institute, McGill University, 3801 rue Université, Montreal, Qc, H3A 2B4, Canada

    Christian Sirard

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  1. Jan Cullingworth
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  2. Martin L Hooper
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Correspondence to Martin L Hooper.

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Cullingworth, J., Hooper, M., Harrison, D. et al. Carcinogen-induced pancreatic lesions in the mouse: effect of Smad4 and Apc genotypes. Oncogene 21, 4696–4701 (2002). https://doi.org/10.1038/sj.onc.1205673

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