Clues from Experimental Models

  • Daniel S. Longnecker


Selecting or creating an animal model of carcinoma of the pancreas is a complex process. One must ask what is being modeled. The reflex response is “ductal adenocarcinoma,” because this is the most common histologic type of pancreatic cancer. However, a recently revised classification of neoplasms of the exocrine pancreas in humans lists 17 major types and 11 subtypes (1). These are grouped into three categories according to clinical behavior (benign, borderline, and malignant). The complexity is reduced somewhat by the fact that several histologic phenotypes have benign or borderline and malignant counterparts that apparently represent sequential steps in the development of a fully malignant phenotype. For example, one group includes mucinous cystadenoma, mucinous cystic tumor with moderate dysplasia, and mucinous cystadenocarcinoma. In such cases, one might anticipate that a single animal model would cover the spectrum of several types of human tumors.


Acinar Cell Pancreatic Carcinoma Acinar Cell Carcinoma Mucinous Cystic Tumor Syrian Golden Hamster 
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  1. 1.
    Klöppel G, Solcia E, Longnecker DS, Capella C, and Sobin LH. Histologic typing of tumours of the exocrine pancreas. Springer-Verlag, New York, 1996.CrossRefGoogle Scholar
  2. 2.
    Caldas C and Kern SE. K-ras mutation and pancreatic adenocarcinoma: state-of-the-art. Int J Pancreatol 1995; 18: 1–6.PubMedGoogle Scholar
  3. 3.
    Pour PM. Modification of tumor development in the pancreas. Prog Exp Tumorx Res 1991; 33:108–131.Google Scholar
  4. 4.
    Kokkinakis DM and Albores-Saavedra J. Orotic acid enhancement of preneoplastic and neoplastic lesions induced in the pancreas and liver of hamsters by N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine. Cancer Res 1994; 54:5324–5332.PubMedGoogle Scholar
  5. 5.
    Sugio K, Gazdar AF, Albores-Saavedra J, and Kokkinakis DM. High yields of K-ras mutations in intraductal papillary mucinous tumors and invasive adenocarcinomas induced by N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine in the pancreas of female Syrian hamsters. Carcinogenesis 1996; 17:303–309.PubMedCrossRefGoogle Scholar
  6. 6.
    Longnecker DS. The azaserine-induced model of pancreatic carcinogenesis in rats. In: D. G. Scarpelli, J. K. Reddy and D. S. Longnecker (eds), Experimental pancreatic carcinogenesis, CRC, Boca Raton, FL, 1987; pp. 117–130.Google Scholar
  7. 7.
    Longnecker DS, Roebuck BD, Yager JD, Jr., Lilja HS, and Siegmund B. Pancreatic carcinoma in azaserine-treated rats: induction, classification and dietary modulation of incidence. Cancer 1981; 47:1562–1572.PubMedCrossRefGoogle Scholar
  8. 8.
    Longnecker DS. Experimental models of exocrine pancreatic tumors. In: Go VLW, Brooks FP, Di Magno EP, Gardner JD, Lebenthal E, and Scheele GA (eds), The exocrine pancreas: biology, pathobiology and diseases, Raven, New York, 1986; pp. 443–458.Google Scholar
  9. 9.
    Longnecker DS. Experimental models of exocrine pancreatic tumors. In: Go VLW, Di-Magno EP, Gardner JD, Lebenthal E, Reber HA, and Scheele GA (eds), The exocrine pancreas: biology, pathobiology, and diseases, Raven, New York, 1993; pp. 551–564.Google Scholar
  10. 10.
    Longnecker DS. Experimental models of endocrine tumors of the pancreas. In: Mignon M, and Jensen RT (eds), Frontiers of gastrointestinal research, Karger, Basel, 1995; pp. 70–83.Google Scholar
  11. 11.
    Dissin J, Mills LR, Mains DL, Black O, and Webster PD. Experimental induction of pancreatic adenocarcinoma in rats. J Natl Cancer Inst 1975; 55:857–864.PubMedGoogle Scholar
  12. 12.
    Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP, and Schabel FM, Jr, Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 1984; 44:714–726.Google Scholar
  13. 13.
    Kamano T, Tamura J, Uchida T, Kanno T, Sakakibara N, Tsutsumi M, Maruyama H, and Konishi Y. Studies by pancreatography of ductal changes induced by administration of pancreatic carcinogen in two dogs. Jpn J Clin Oncol 1991; 21:282–286.PubMedGoogle Scholar
  14. 14.
    Schüller HM, Jorquera R, Reichert A, and Castonguay A. Transplacental induction of pancreas tumors in hamsters by ethanol and the tobacco-specific nitrosamine 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone. Cancer Res 1993; 53:2498–2501.PubMedGoogle Scholar
  15. 15.
    Schaeffer BK, Wiebkin P, Longnecker DS, Coon CI, and Curphey TJ. DNA damage produced by N-nitrosomethyl(2-oxopropyl)amine (MOP) in hamsters and rat pancreas: a role for the liver. Carcinogenesis 1984; 5:565–570.PubMedCrossRefGoogle Scholar
  16. 16.
    Wiebkin P, Schaeffer BK, Longnecker DS, and Curphey TJ. Oxidative and conjugative metabolism of xenobiotics by isolated rat and hamster acinar cells. 1984; 12:427–431.Google Scholar
  17. 17.
    Kokkinakis DM, Reddy MK, Norgle JR, and Baskaran K. Metabolism and activation of pancreas specific nitrosamines by pancreatic ductal cells in culture. Carcinogenesis 1993; 14:1705–1709.PubMedCrossRefGoogle Scholar
  18. 18.
    Kokkinakis DM and Subbarao V. The significance of DNA damage, its repair and cell proliferation during carcinogen treatment in the initiation of pancreatic cancer in the hamster model. Cancer Res 1993; 53:2790–2795.PubMedGoogle Scholar
  19. 19.
    Zurlo J, Curphey TJ, and Longnecker DS. Identification of 7-carboxy-methylguanine in DNA from pancreatic acinar cells exposed to azaserine. Cancer Res 1982; 42:1286–1288.PubMedGoogle Scholar
  20. 20.
    Konishi Y. Carcinogenic activity of endogenously synthesized N-nitrosobis(2-hydropropyl)amine in rats. IARC Sci Publ 1991; 105:318–321.PubMedGoogle Scholar
  21. 21.
    Lawson T. and Kolar CH. Xenobiotic metabolism and toxic responses in pancreatic duct epithelial cells. In: Sirica AE and Longnecker DS (eds), Biliary and pancreatic ductal epithelia. Pathobiology and pathophysiology, Marcel Dekker, New York, 1997; pp. 443–455.Google Scholar
  22. 22.
    Yanagisawa A, Ohtake K, Ohashi K, Hori M, Kitagawa T, Sugano H, and Kato Y. Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res 1993; 53:953–956.PubMedGoogle Scholar
  23. 23.
    Pour PM, Konishi Y, Klöppel G, and Longnecker DS (eds), Atlas of exocrine pancreatic tumors. Springer-Verlag, Tokyo, 1994.Google Scholar
  24. 24.
    Fujii H, Egami H, Pour P, and Pelling J. Pancreatic ductal adenocarcinomas induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine contain a c-Ki-ras oncogene with a point-mutated codon 12. Mol Carc 1990; 3:296–301.CrossRefGoogle Scholar
  25. 25.
    Cerny WL, Mangold KA, and Scarpelli DG. Activation of K-ras during N-nitrosobis(2-oxopropyl)amine induced pancreatic carcinogenesis. Proc Am Assoc Cancer Res 1991; 32:138.Google Scholar
  26. 26.
    Ushijima T, Tsutsumi M, Sakai R, Ishizaka Y, Takaku F, Konishi Y, et al. Ki-ras activation in pancreatic carcinomas of Syrian hamsters induced by N-nitrosobis(2-hydroxypropyl)amine. Jpn J Cancer Res 1991; 82:965-968.Google Scholar
  27. 27.
    Chang KW, Laconi S, Mangold KA, Hubchak S, and Scarpelli DG. Multiple genetic alterations in hamster pancreatic ductal adenocarcinomas. Cancer Res 1995; 55:2560–2568.PubMedGoogle Scholar
  28. 28.
    Tsutsumi M, Kondoh S, Noguchi O, Horiguchi K, Kobayashi E, Okita S, et al. K-ras gene mutation in early ductal lesions induced in a rapid production model for pancreatic carcinomas in Syrian hamsters. Jpn J Cancer Res 1993; 84:1101–1105.PubMedCrossRefGoogle Scholar
  29. 29.
    Ornitz DM, Hammer RE, Messing A, Palmiter RD, and Brinster RL. Pancreatic neoplasia induced by SV40 T antigen expression in acinar cells of transgenic mice. Science 1987; 238:188–193.PubMedCrossRefGoogle Scholar
  30. 30.
    Terhune PG, Heffess C, and Longnecker DS. Human pancreatic acinar cell carcinomas contain only wild-type c-K-ras codons 12, 13 and 61. Mol Carcinog 1994; 10:110–114.PubMedCrossRefGoogle Scholar
  31. 31.
    Schaeffer BK, Zurlo J, and Longnecker DS. Activation of c-K-ras not detectable in adenomas or adenocarcinomas arising in rat pancreas. Mol Carcinog 1990; 3:165–170.PubMedCrossRefGoogle Scholar
  32. 32.
    van Kranen HJ, Vermeulen E, Schoren L, Bax J, Woutersen RA, van Iersel P, van Kreijl CF, and Scherer E. Activation of c-K-ras is frequent in pancreatic carcinomas of Syrian hamsters, but is absent in pancreatic tumors of rats. Carcinogenesis 1991; 12:1477–1482.PubMedCrossRefGoogle Scholar
  33. 33.
    Schaeffer BK, Terhune PG, and Longnecker DS. Pancreatic carcinomas of acinar and mixed acinar/ductal phenotypes in Ela-1-myc transgenic mice do not contain c-K-ras mutations. Am J Pathol 1994; 145:696–701.PubMedGoogle Scholar
  34. 34.
    Kuhlmann ET, Terhune PG, and Longnecker DS. Evaluation of c-K-ras in pancreatic carcinomas from Ela-l-SV40T transgenic mice. Carcinogenesis 1993; 14:2649–2651.PubMedCrossRefGoogle Scholar
  35. 35.
    Okita S, Tsutsumi M, Onji M, and Konishi Y. p53 mutation without allelic loss and absence of mdm-2 amplification in a transplantable hamster pancreatic ductal adenocarcinoma and derived cell lines but not primary ductal adenocarcinomas in hamsters. Mol Carcin 1995; 13:266–271.CrossRefGoogle Scholar
  36. 36.
    Chang KW, Mangold KA, Hubchak S, Laconi S, and Scarpelli DG. Genomic p53 mutation in a chemically induced hamster pancreatic ductal adenocarcinoma. Cancer Res 1994; 54:3878–3883.PubMedGoogle Scholar
  37. 37.
    Terhune PG and Longnecker DS. Do oncogene and tumor suppressor gene abnormalities vary with type of carcinoma of the pancreas? J Hep Bil Pancr Surg 1995; 2:1–7.CrossRefGoogle Scholar
  38. 38.
    . Kruse F, Rose SD, Swift GH, Hammer RE, and MacDonald RJ. An endocrine-specific element is an integral component of an exocrine-specific pancreatic enhancer. Genes Dev 1993; 7:774–786.PubMedCrossRefGoogle Scholar
  39. 39.
    Bell RH, Jr, Memoli VA, and Longnecker DS. Hyperplasia and tumors of the islets of Langerhans in mice bearing an elastase I-SV40 T-antigen fusion gene. Carcinogenesis 1990;11:1393–1398.Google Scholar
  40. 40.
    Glasner S, Memoli V, and Longnecker DS. Characterization of the ELSV transgenic mouse model of pancreatic carcinoma: histologic type of large and small tumors. Am J Pathol 1992; 140:1237–1245.PubMedGoogle Scholar
  41. 41.
    Sandgren EP, Quaife CJ, Paulovich AG, Palmiter RD, and Brinster RL. Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci USA 1991; 88:93–97.PubMedCrossRefGoogle Scholar
  42. 42.
    Visser CJ, Bruggink AH, Korc M, Kobrin MS, de Weger RA, Seifert-Bock I, et al. Over-expression of transforming growth factor-alpha and epidermal growth factor receptor, but not epidermal growth factor, in exocrine pancreatic tumours in hamsters. Carcinogenesis 1996; 17:779–785.PubMedCrossRefGoogle Scholar
  43. 43.
    Visser CJ, Woutersen RA, Bruggink AH, van Garderen-Hoetmer A, Seifert-Bock I, Tilanus MG, and de Weger RA. Transforming growth factor-alpha and epidermal growth factor expression in the exocrine pancreas of azaserine-treated rats: modulation by cholecystokinin or a low fat, high fiber (caloric restricted) diet. Carcinogenesis 1995; 16:2075–2082.PubMedCrossRefGoogle Scholar
  44. 44.
    Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, and Lee DC. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990;61: 1121–1135.PubMedCrossRefGoogle Scholar
  45. 45.
    Sandgren EP, Luetteke NC, Qiu TH, Palmiter RD, Brinster RL, and Lee DC. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 1993; 13: 320–330.PubMedGoogle Scholar
  46. 46.
    Bockman DE. Cells of origin of pancreatic cancer: experimental animal tumors related to human pancreas. Cancer 1981; 47:1528–1534.PubMedCrossRefGoogle Scholar
  47. 47.
    Pour PM and Kazakoff K. Stimulation of islet cell proliferation enhances pancratic ductal carcinogenesis in the hamster model. Am J Pathol 1996; 149:1017–1025.PubMedGoogle Scholar
  48. 48.
    Longnecker DS, Roebuck BD, Kuhlmann ET, and Curphey TJ. Induction of pancreatic carcinomas in rats with N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine: histopathology. J Natl Cancer Inst 1985; 74: 209–217.PubMedGoogle Scholar
  49. 49.
    Longnecker DS, Curphey TJ, Kuhlmann ET, and Schaeffer BK. Experimental induction of pancreatic carcinoma in the hamster with Nδ-(iV-methyl-N-nitrosocarbamoyl)-L-ornithine. J Natl Cancer Inst 1983; 71:1327–1336.PubMedGoogle Scholar
  50. 50.
    Longnecker DS, Curphey TJ, Lilja HS, French JI, and Daniel DS. Carcinogenicity in rats of the nitrosourea amino acid Nδ-(N-methyl-TV-nitrosocarbamoy1)-L-orithine. J Env Path Toxicol 1980; 4:117–129.Google Scholar
  51. 51.
    Longnecker DS, Kato Y, Konishi Y, Freeman D, Glasner S, Memoli VA, et al. Comparison of histologic type and stage of exocrine pancreatic neoplasms from surgical series in Europe, Japan and the United States. In: Beger H, Büchler M, and Schoenberg MH. (eds), Cancer of the pancreas: molecular biology, progress in diagnosis and treatment, Springer-Verlag, Heidelberg, 1996; pp. 47–54.Google Scholar
  52. 52.
    Longnecker DS, Kuhlmann ET, and Freeman DH, Jr. Characterization of the elastase-1 S V40 T-antigen mouse model of pancreatic carcinoma: effects of sex and diet. Cancer Res 1990;50:7552–7554.Google Scholar
  53. 53.
    Roebuck BD, Yager JD, Jr. Longnecker DS, and Wilpone SA. Promotion by unsaturated fat of azaserine-induced pancreatic carcinogenesis in the rat. Cancer Res 1981; 41:3961–3966.PubMedGoogle Scholar
  54. 54.
    Birt DF, Patil K, and Pour PM. Comparative studies on the effects of semipurified and commercial diet on the longevity and spontaneous and induced lesions in the Syrian Golden Hamster. Nutr Cancer 1985; 7:167–177.PubMedCrossRefGoogle Scholar
  55. 55.
    Appel MJ and Woutersen RA. Effects of dietary fish oil (MaxEPA) on Af-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinogenesis in hamsters. Cancer Lett 1995; 94:179–189.PubMedCrossRefGoogle Scholar
  56. 56.
    Lhoste EF, Roebuck BD, and Longnecker DS. Stimulation of the growth of azaserine-induced nodules in the rat pancreas by dietary camostate (FOY-305). Carcinogenesis 1988; 9:901–906.PubMedCrossRefGoogle Scholar
  57. 57.
    Spannagel AW, Green GM, Guan D, Liddle RA, Faull K, and Reeve J., Jr, Purification and characterization of a luminal cholecystokinin-releasing factor from rat intestinal secretion. Proc Natl Acad Sci USA, 1996; 93:4415–4420.PubMedCrossRefGoogle Scholar
  58. 58.
    Bell RH, Kuhlmann ET, Jensen RT, and Longnecker DS. Overexpression of cholecystokinin receptors in azaserine-induced neoplasms of the rat pancreas. Cancer Res 1992; 52:3295–3299.PubMedGoogle Scholar
  59. 59.
    Povoski SP, Zhou W, Longnecker DS, Roebuck BD, and Bell RH, Jr. Stimulation of growth of azaserine-induced putative preneoplastic lesions in rat pancreas is mediated specifically by way of cholecystokinin-A receptors. Cancer Res 1993; 53:3925–3929.PubMedGoogle Scholar
  60. 60.
    Kennedy AR. Prevention of carcinogenesis by protease inhibitors. Cancer Res 1994; 54(Suppl):1999s–2005s.Google Scholar
  61. 61.
    Longnecker DS, Kuhlmann ET, and Curphey TJ. Divergent effects of retinoids on pancreatic and liver carcinogenesis in azaserine-treated rats. Cancer Res 1983; 43:3219-3225.Google Scholar
  62. 62.
    Clapper ML, Wood M, Leahy K, Lang D, Miknyoczki S, and Ruggeri BA. Chemopreventive activity of Oltipraz against N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic carcinoma development and effects on survival of Syrian golden hamsters. Carcinogenesis 1995; 16:2159–2165.PubMedCrossRefGoogle Scholar
  63. 63.
    Appel MJ, van Garderen-Hoetmer A, and Woutersen RA. Lack of inhibitory effects of betacarotene, vitamin C, vitamin E and selenium on development of ductular adenocarcinomas in exocrine pancreas of hamsters. Cancer Lett 1996; 103:157–162.PubMedCrossRefGoogle Scholar
  64. 64.
    Longnecker DS. Experimental pancreatic cancer: role of species, sex and diet. Bull Cancer 1990; 77:27–37.PubMedGoogle Scholar
  65. 65.
    Lhoste EF, Roebuck BD, Brinck-Johnsen T, and Longnecker DS. Effects of castration and hormone replacement on azaserine-induced pancreatic carcinogenesis in male and female Fischer rats. Carcinogenesis 1987; 8:699–703.PubMedCrossRefGoogle Scholar
  66. 66.
    Visser CJ, Meijers M, van Garderen-Hoetmer A, Klijn JG, Foekens JA, and Woutersen RA. Effects of aminoglutethimide, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters. Int J Cancer 1995; 63:732–737.PubMedCrossRefGoogle Scholar
  67. 67.
    Szepeshazi K, Schally AV, Cai RZ, Radulovic S, Milovanovic S, and Szoke B. Inhibitory effect of bombesin/gastrin-releasing peptide antagonist RC-3095 and high dose of somatostatin analogue RC-160 on nitrosamine-induced pancreatic cancers in hamsters. Cancer Res 1991; 51:5980–5986.PubMedGoogle Scholar
  68. 68.
    Szepeshazi K, Halmos G, Groot K, and Schally AV. Combination treatment of nitrosamine-induced pancreatic cancers in hamsters with analogs of LH-RH and a bombesin/GRP antagonist. Int J Pancreatol 1994; 16:141–149.Google Scholar
  69. 69.
    Qin Y, Ertl T, Cai RZ, Halmos G, and Schally AV. Inhibitory effect of bombesin receptor antagonist RC-3095 on the growth of human pancreatic cancer cells in vivo and in vitro. Cancer Res 1994; 54:1035–1041.PubMedGoogle Scholar
  70. 70.
    Douglas BR, Woutersen RA, Jansen JBMJ, de Jong AJL, Rovati LC, and Lamers CBHW. Modulation by CR-1409 (Lorglumide), a cholecystokinin receptor antagonist, of trypsin inhibitor-enhanced growth of azaserine-induced putative preneoplastic lesions in rat pancreas. Cancer Res 1989; 49:2438–2441.PubMedGoogle Scholar
  71. 71.
    Lhoste EF, and Longnecker DS. Effect of bombesin and caerulein on early stages of carcinogenesis induced by azaserine in the rat pancreas. Cancer Res 1987; 47:3273–3277.PubMedGoogle Scholar
  72. 72.
    Scorsone KA, Zhou, Y-Z, Butel JS, and Slagle BL. p53 Mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res 1992; 52:1635–1638.PubMedGoogle Scholar
  73. 73.
    Levison DA, Morgan RGH, Brimacombe JS, Hopwood D, Coghill G, and Wormsley KG. Carcinogenic effects of di(2-hydroxypropyl)nitrosamine (DHPN) in male Wistar rats: promotion of pancreatic cancer by a raw soya flour diet. Scand J Gastroenterol 1979; 14:217–224.PubMedCrossRefGoogle Scholar
  74. 74.
    Reddy JK and Rao MS. Transplantable adenocarcinoma in inbred guinea pigs induced by N-methyl-N-nitrosourea. Cancer Res 1975; 35:2269–2277.PubMedGoogle Scholar
  75. 75.
    Furukawa F, Sato H, Imaida K, Toyoda K, Imazawa T, Takahashi M, and Hayashi Y. Induction of pancreatic tumors in male Syrian golden hamsters by intraperitoneal N-methyl-N-nitrosourea injection. Pancreas 1992; 7:153–158.PubMedCrossRefGoogle Scholar
  76. 76.
    Rivenson A, Hoffmann D, Prokopczyk B, Amin S, and Hecht SS. Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and areca-derived N-nitrosamines. Cancer Res 1988; 48:6912–1917.PubMedGoogle Scholar
  77. 77.
    Pour PM. and Rivenson A. Induction of a mixed ductal-squamous-islet cell carcinoma in a rat treated with a tobacco-specific carcinogen. Am J Pathol 1989; 134:627–631.PubMedGoogle Scholar

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  • Daniel S. Longnecker

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