Experimental animal models of pancreatic carcinogenesis and metastasis

  • Daoyan Wei
  • Henry Q. Xiong
  • James L. Abbruzzese
  • Keping Xie
Review Article


Pancreatic cancer is a lethal disease characterized by early metastasis, local invasion, and resistance to conventional therapies. To understand its etiology and eventually make prevention of it possible and effective, appropriate carcinogenesis models will certainly help us understand the effects of environmental and genetic elements on pancreatic carcinogenesis. The development of new treatment strategies to control cancer metastasis is of immediate urgency. Fulfillment of this task relies on our knowledge of the cellular and molecular biology of pancreatic cancer metastasis and the availability of biologically and clinically relevant model systems. Many of the existing pancreatic cancer carcinogenesis and metastasis animal models are described in this review. The advantages and disadvantages of each model and their clinical implications are discussed, and special attention is focused on experimental therapeutic strategies targeting pancreatic cancer metastasis.

Key Words

Carcinogenesis metastasis tumor pancreas 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    America Cancer Society 2002, Cancer Facts & Figures, American Cancer Society, Atlanta, GA.Google Scholar
  2. 2.
    Evans DB, Abbruzzese JL, Rich TR. Cancer of the pancreas, in Cancer Principles and Practice of Oncology, 5th ed, De Vita VT, Hellman S, Rosenberg SA, eds. 1997; pp. 1054–1087.Google Scholar
  3. 3.
    Gold EB, Goldin SB. Epidemiology of and risk factors for pancreatic cancer. Surg Oncol Clin N Am 1998;7:67–91.PubMedGoogle Scholar
  4. 4.
    Ettinghausen SE, Schwartzentruber DJ, Sindelar WF. Evolving strategies for the treatment of adenocarcinoma of the pancreas. J Clin Gastroenterol 1995;21:48–60.PubMedGoogle Scholar
  5. 5.
    Pour PM. Experimental panceratic cancer. Am J Surg Pathol 1989;13:96–103.PubMedGoogle Scholar
  6. 6.
    Hall PA, Lemoine NR. Models of pancreatic cancer. Cancer Surv 1993;16:135–155.PubMedGoogle Scholar
  7. 7.
    Torrisani J, Buscail L. Molecular pathways of pancreatic carcinogenesis. Ann Pathol. 2002;22(5):349–355.PubMedGoogle Scholar
  8. 8.
    Watanapa P, Williamson RC. Experimental pancreatic hyperplasia and neoplasia: effects of dietary and surgical manipulation. Br J Cancer 1993;67(5):877–884.PubMedGoogle Scholar
  9. 9.
    Rao MS. Animal models of exocrine pancreatic carcinogenesis. Cancer Metastasis Rev 1987;6(4):665–676.PubMedGoogle Scholar
  10. 10.
    Longnecker DS. Carcinogenesis of the pancreas. Arch Pathol Lab Med 1983;107:54–58.PubMedGoogle Scholar
  11. 11.
    Pour PM, Wilson R. Experimental tumors of the Panceras. Williams & Wilkins, Baltimore, MD 1980; pp. 37–158.Google Scholar
  12. 12.
    Cerny WL, Mangold KA, Scarpelli DG. Activation of K-ras in transplantable pancreatic ductal adenocarcinomas of Syrian golden hamsters. Carcinogenesis 1990;11(11):2075–2079.PubMedGoogle Scholar
  13. 13.
    Fujii H, Egami H, Chaney W, Pour P, 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 Carcinog 1990;3(5):296–301.PubMedGoogle Scholar
  14. 14.
    Okita S, Tsutsumi M, Onji M, 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 Carcinog 1995;13(4):266–271.PubMedGoogle Scholar
  15. 15.
    Schmied B, Liu G, Moyer MP, Hernberg IS, Sanger W, Batra S, Pour PM. Induction of adenocarcinoma from hamster panceratic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro. Carcinogenesis 1999;20:317–324.PubMedGoogle Scholar
  16. 16.
    Longnecker DS. The quest for preneoplastic lesions in the pancreas. Arch Pathol Lab Med 1994;118(3):226.PubMedGoogle Scholar
  17. 17.
    Longnecker D. Experimental pancreatic cancer: Role of species, sex and diet. Bull Cancer 1990;77:27–37.PubMedGoogle Scholar
  18. 18.
    Hotz HG, Hines OJ, Foitzil T, Reber HA. Animal models of exocrime pancreatic cancer. Int J Colorectal Dis 2000;15:136–143.PubMedGoogle Scholar
  19. 19.
    Terhune PG, Phifer DM, Tosteson TD, Longnecker DS. K-ras mutation in focal proliferative lesions of human pancreas. Cancer Epidemiol Biomarkers Prev 1998;7(6):515–521.PubMedGoogle Scholar
  20. 20.
    Terhune PG, Heffess CS, Longnecker DS. Only wild-type c-Ki-ras codons 12, 13, and 61 in human pancreatic acinar cell carcinomas. Mol Carcinog 1994;10(2):110–114.PubMedGoogle Scholar
  21. 21.
    Longnecker DS, Pettengill OS, Davis BH, Schaeffer BK, Zurlo J, Hong HL, Kuhlmann ET. Characterization of preneoplastic and neoplastic lesions in the rat pancreas. Am J Pathol 1991;138(2):333–340.PubMedGoogle Scholar
  22. 22.
    Reber HA, Hotz B, Foitzik T, Buhr HJ, Cortina G, Hines OJ. An improved clinical model of orthotopic pancreatic cancer in immunocompetent Lewis rats. Pancreas 2001;22(2):113–21PubMedGoogle Scholar
  23. 23.
    Roebuck BD, Longnecker DS. Species and rat strain variation in panceratic nodule induction by azaserine. J Natl Cancer Inst 1977;59:1273–1277.PubMedGoogle Scholar
  24. 24.
    Zimmerman JA, Trombetta LD, Carter TH, Weisbroth SH. Panceratic carcinoma induced by N-methyl-n -nitrosourea in aged mice. Gerontology 1982;28:114–120.PubMedCrossRefGoogle Scholar
  25. 25.
    Rao MS, Subbarao V, Scarpelli DG. Atypical acinar cell lesions of the pancreas in mice induced by 4-hydorxyaminoquinoline-1-oxide. Int J Pancreatol 1987;2:1–10.PubMedGoogle Scholar
  26. 26.
    Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP, Schabel FM. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 1984;44:717–726.PubMedGoogle Scholar
  27. 27.
    Kern SE. Molecular genetic alterations in ductal pancreatic adenocarcinomas. Med Clin North Am 2000;84(3):691–695.PubMedGoogle Scholar
  28. 28.
    Cardiff RD, Leder A, Kuo A, Pattengale PK, Leder P. Multiple tumor types appear in a transgenic mouse with the ras oncogene. Am J Pathol 1993;142(4):1199–1207.PubMedGoogle Scholar
  29. 29.
    Ornitz DM, Hammer RE, Messing A, Palmiter RD, Brinster RL. Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice. Science 1987;238(4824):188–193.PubMedGoogle Scholar
  30. 30.
    Glasner S, Memoli V, Longnecker DS. Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors. Am J Pathol 1992;140(5):1237–1245.PubMedGoogle Scholar
  31. 31.
    Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 1990;61(6):1121–1135.PubMedGoogle Scholar
  32. 32.
    Sandgren EP, Luetteke NC, Qiu TH, Palmiter RD, Brinster RL, Lee DC. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 1993;13(1):320–330.PubMedGoogle Scholar
  33. 33.
    Kuhlmann E, Terhune PG, Longnecker DS. Evaluation of c-K-ras in pancreatic carcinomas from Ela-1, SV40E transgenic mice. Carcinogenesis 1993;14(12):2649–2651.PubMedGoogle Scholar
  34. 34.
    Schaeffer BK, Terhune PG, 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(3):696–701.PubMedGoogle Scholar
  35. 35.
    Quaife CJ, Pinkert CA, Ornitz DM, Palmiter RD, Brinster RL. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell 1987;48(6):1023–1034.PubMedGoogle Scholar
  36. 36.
    Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 1990;61(6):1137–1146.PubMedGoogle Scholar
  37. 37.
    Alves F, Contag S, Missbach M, et al. An orthotopic model of ductal adenocarcinoma of the pancreas in severe combined immunodeficient mice representing all steps of the metastatic cascade. Pancreas 2001;23(3):227–235.PubMedGoogle Scholar
  38. 38.
    Fidler IJ Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 1990;50(19):6130–6138.PubMedGoogle Scholar
  39. 39.
    Sugarbaker EV. Cancer metastasis: a product of tumor-host interactions. Curr Probl Cancer 1979;3:1–59.PubMedGoogle Scholar
  40. 40.
    Xie K, Huang S. Regulation of cancer metastasis by stress pathways. Clinical Expl Metastasis 2003;20:31–43.Google Scholar
  41. 41.
    Korc, M. Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 1998;7(1):25–41.PubMedGoogle Scholar
  42. 42.
    Terhune PG, Heffess CS, Longnecker DS. Only wild-type c-Ki-ras codons 12, 13, and 61 in human pancreatic acinar cell carcinomas. Mol Carcinog 1994;10(2):110–114.PubMedGoogle Scholar
  43. 43.
    Cerny WL, Mangold KA, Scarpelli DG. Activation of K-ras in transplantable pancreatic ductal adenocarcinomas of Syrian golden hamsters. Carcinogenesis 1990;11(11):2075–2079.PubMedGoogle Scholar
  44. 44.
    Fujii H, Egami H, Chaney W, Pour P, 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 Carcinog 1990;3(5):296–301.PubMedGoogle Scholar
  45. 45.
    Okita S, Tsutsumi M, Onji M, 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 Carcinog 1995;13(4):266–271.PubMedGoogle Scholar
  46. 46.
    Kern SE. Advances from genetic clues in pancreatic cancer. Curr Opin Oncol 1998;10:74–80.PubMedGoogle Scholar
  47. 47.
    Folkman J. Tumor angiogenesis and tissue factor. Nat Med 1996;2(2):167–168.PubMedGoogle Scholar
  48. 48.
    Leek RD, Harris AL, Lewis CE. Cytokine networks in solid human tumors: regulation of angiogenesis. J Leukoc Biol 1994;56:423–435.PubMedGoogle Scholar
  49. 49.
    Brown LF, Detmar K, Claffey JA, Nagy D, Feng AM, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: A multifunctional angiogenic cytokine. in Regulation of Angiogenesis. Goldberg ID, Rosen EM, eds. Birkhauser Verlag Basel Switzerland. 1997 pp. 233–270.Google Scholar
  50. 50.
    Itakura J, Ishiwata T, Friess H, Fujii H, Matsumoto Y, Buchler MW Korc M. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 1997;3:1309–1316.PubMedGoogle Scholar
  51. 51.
    Yamanaka Y, Friess H, Buchler M, et al. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 1993;53(21):5289–5296.PubMedGoogle Scholar
  52. 52.
    Shi Q, Abbruzzese J, Huang S, Fidler IJ, Xie K. Constitutive and inducible interleukin-8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 1999;5:3711–3721.PubMedGoogle Scholar
  53. 53.
    Le X, Shi Q, Wang B, et al. Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interferon Cytokine Res 2000;20:1532–1540.Google Scholar
  54. 54.
    Xie K. Interleukin-8 and Human Cancer Biology. Cytokine Growth Factor 2000;12(4):375–391.Google Scholar
  55. 55.
    Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res 1991;51:5054s-5059s.PubMedGoogle Scholar
  56. 56.
    Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989;49:6449–6465.PubMedGoogle Scholar
  57. 57.
    Boucher Y, Baxter LT, Jain RK. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 1990;50:4478–4484.PubMedGoogle Scholar
  58. 58.
    Gasic GJ: Role of plasma, platelets and endothelial cells in tumormetastasis. Cancer Metastasis Rev 1984;3:99–105.PubMedGoogle Scholar
  59. 59.
    Fidler IJ, Bucana C. Mechanism of tumor cell resistance to lysis by syngeneic lymphocytes. Cancer Res 1977;37:3945–3956.PubMedGoogle Scholar
  60. 60.
    Fidler IJ Metastasis: Quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2-deoxyuridine. J Natl Cancer Inst 1970;46:773–783.Google Scholar
  61. 61.
    Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997;89:1260–1270PubMedGoogle Scholar
  62. 62.
    Zetter BR. The cellular basis of site-specific tumor metastasis. N Engl J Med 1990;322(9):605–612.PubMedCrossRefGoogle Scholar
  63. 63.
    Nicolson GL. Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 1988;948:175–208.PubMedGoogle Scholar
  64. 64.
    Xie K, Wang Y, Huang S, et al. Nitric oxide-mediated apoptosis in murine melanma is associated with downregulation of Bcl-2. Oncogene 1997;15(6):771–779.PubMedGoogle Scholar
  65. 65.
    Radinsky R. Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment. Cancer Metastasis Rev 1995;14:323–338.PubMedGoogle Scholar
  66. 66.
    Fidler IJ, Gersten DM, Hart IR. The biology of cancer invasion and metastasis. Adv Cancer Res 1978;28:149–250.PubMedGoogle Scholar
  67. 67.
    Fidler IJ, Kripke ML. Metastasis results from preexisting variant cells within a malignant tumor. Science 1977;197(4306):893–895.PubMedGoogle Scholar
  68. 68.
    Vezeridis MP, Tzanakakis GN, Meitner PA, Doremus CM, Tibbetts LM, Calabresi P. In vivo selection of a highly metastatic cell line from a human pancreatic carcinoma in the nude mouse. Cancer 1992;69(8):2060–2063.PubMedGoogle Scholar
  69. 69.
    Fidler IJ. Selection of successive tumor lines for metastasis. Nat New Biol 1973;242(118):148–149.PubMedGoogle Scholar
  70. 70.
    Bruns CJ, Harbison MT, Kuniyasu H, Eue I, Fidler IJ. In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice. Neoplasia 1999;1(1):50–62.PubMedGoogle Scholar
  71. 71.
    Kripke ML, Gruys E, Fidler IJ. Metastatic heterogeneity of cells from an ultraviolet light-induced murine fibrosarcoma of recent origin. Cancer Res 1978;38:2962–2967.PubMedGoogle Scholar
  72. 72.
    Welch DR. Technical considerations for studying cancer metastasis in vivo. Clin Exp Metastasis 1997;15(3):272–306.PubMedGoogle Scholar
  73. 73.
    Giovanella BC, Yim SO, Stehlin JS, Williams LJ Jr. Development of invasive tumors in the nude mouse after injection of cultured human melanoma cells. J Natl Cancer Inst 1972;48(5):1531–1533.PubMedGoogle Scholar
  74. 74.
    Shimosato Y, Kameya T, Nagai K, Hirohashi S, Koide T, Hayashi H, Nomura T. Transplantation of human tumors in nude mice. J Natl Cancer Inst 1976;56(6):1251–1260.PubMedGoogle Scholar
  75. 75.
    Sharkey FE, Fogh J. Considerations in the use of nude mice for cancer research. Cancer Metastasis Rev 1984;3(4):341–360.PubMedGoogle Scholar
  76. 76.
    Schmied BM, Ulrich AB, Matsuzaki H, et al. Biologic instability of pancreatic cancer xenografts in the nude mouse. Carcinogenesis 2000;21(6):1121–1127.PubMedGoogle Scholar
  77. 77.
    Hotz HG, Reber HA, Hotz B, Foitzik T, Buhr HJ, Cortina G, Hines OJ. An improved clinical model of orthotopic pancreatic cancer in immunocompetent Lewis rats. Pancreas 2001;22(2):113–121.PubMedGoogle Scholar
  78. 78.
    Wang B, Xiong Q, Shi Q, Le X, Abbruzzese JL, Khan N, Xie K. Intact Nitric Oxide Synthase II Gene is Required for Interferon—mediated Suppression of Growth and Metastasis of Pancreatic Adenocarcinoma. Cancer Res 2001;61(1):71–75.PubMedGoogle Scholar
  79. 79.
    Wang B, Shi Q, Abbruzzeze JL, Xiong Q, Le X, Xie K. A novel, clinically relevant animal model of metastatic pancreatic adenocarcinoma biology and therapy. Int J Pancreatol 2001;29(1):37–46.PubMedGoogle Scholar
  80. 80.
    Siedlar M, Stachura J, Szczepanik A, et al. Characterization of human pancreatic adenocarcinoma cell line with high metastatic potential in SCID mice. Invasion Metastasis 1995;15(1–2):60–69.PubMedGoogle Scholar
  81. 81.
    Tan MH, Chu TM Characterization of the tumorigenic and metastatic properties of a human pancreatic tumor cell line (AsPC-1) implanted orthotopically into nude mice. Tumor Biol 1985;6(1):89–98.Google Scholar
  82. 82.
    Fidler IJ Orthotopic implantation of human colon carcinomas into nude mice provides a valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev 1991;10(3):229–243.PubMedGoogle Scholar
  83. 83.
    Outzen HC, Custer RP. Growth of human normal and neoplastic mammary tissues in the cleared mammary fat pad of the nude mouse. J Natl Cancer Inst 1975;55(6):1461–1466.PubMedGoogle Scholar
  84. 84.
    Kameya T, Shimosato Y, Tumuraya M, Ohsawa N, Nomura T. Human gastric choriocarcinoma serially transplanted in nude mice. J Natl Cancer Inst 1976;56(2):325–332.PubMedGoogle Scholar
  85. 85.
    Sharkey FE, Fogh J. Considerations in the use of nude mice for cancer research. Cancer Metastasis Rev 1984;3(4):341–360.PubMedGoogle Scholar
  86. 86.
    Stanbridge EJ, Perkins FT. Tumourigenicity testing in immunosuppressed mice: advantages and disadvantages. Dev Biol Stand 1976;13–15;37: 211–217.Google Scholar
  87. 87.
    Fidler IJ. Modulation of the organ microenvironment for treatment of cancer metastasis. J Natl Cancer Inst 1995;87(21):1588–1592.PubMedGoogle Scholar
  88. 88.
    Slack NH, Bross ID. The influence of site of metastasis on tumour growth and response to chemotherapy. Br J Cancer 1975;32(1):78–86.PubMedGoogle Scholar
  89. 89.
    Xie K, Huang S, Dong Z, Gutman M, Fidler IJ. Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP31362. Cancer Res 1995;55(14):3123–3131.PubMedGoogle Scholar
  90. 90.
    Vezeridis MP, Meitner PA, Tibbetts LM, Doremus CM, Tzanakakis G, Calabresi P. Heterogeneity of potential for hematogenous metastasis in a human pancreatic carcinoma. J Surg Res 1990;48(1):51–55.PubMedGoogle Scholar
  91. 91.
    Lafreniere R, Rosenberg SA. A novel approach to the generation and identification of experimental hepatic metastases in a murine model. J Natl Cancer Inst 1986;76(2):309–322.PubMedGoogle Scholar
  92. 92.
    Koike A, Nakazato H, Moore GE. The fate of Ehrlich cells injected into the portal system. Cancer 1963;16:716–720.PubMedGoogle Scholar
  93. 93.
    Kopper L, Van Hanh T, Lapis K. Experimental model for liver metastasis formation using Lewis lung tumor. J Cancer Res Clin Oncol 1982;103(1):31–38.PubMedGoogle Scholar
  94. 94.
    Marincola F, Taylor-Edwards C, Drucker B, Holder WD Jr. Orthotopic and heterotopic xenotransplantation of human pancreatic cancer in nude mice. Curr Surg 1987;44(4):29,429–29,437.Google Scholar
  95. 95.
    Vezeridis MP, Doremus CM, Tibbetts LM, Tzanakakis G, Jackson BT. Invasion and metastasis following orthotopic transplantation of human pancreatic cancer in the nude mouse. J Surg Oncol 1989;40(4):261–265.PubMedGoogle Scholar
  96. 96.
    Furukawa T, Kubota T, Watanabe M, Kitajima M, Hoffman RM. A novel patient-like treatment model of human pancreatic cancer constructed using orthotopic trans-plantation of histologically intact human tumor tissue in nude mice. Cancer Res 1993;53(13):3070–3072.PubMedGoogle Scholar
  97. 97.
    Fu X, Guadagni F, Hoffman RM. A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci USA 1992;89(12):5645–5649.PubMedGoogle Scholar
  98. 98.
    Fidler IJ, Hart IR. Biologic diversity in metastatic neoplasms-origins and implications. Science 1982;217:998–1001.PubMedGoogle Scholar
  99. 99.
    Bouvet M, Wang J, Stephanie RN, et al. Real-Time optical imaging of primary tumor growth and multiple metastatic events in a pancreatic cancer orthotopic model. Cancer Res 2002;62:1534–1540.PubMedGoogle Scholar
  100. 100.
    Yang M, Baranov E, Wang JW, et al. Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proc Natl Acad Sci U S A 2002;99(6):3824–3829.PubMedGoogle Scholar
  101. 101.
    Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia. 2001;15(6):875–890.PubMedGoogle Scholar
  102. 102.
    Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS. Radiosensitization of pancreatic cancer cells by 2,2-difluoro-2 -deoxycytidine. Int J Radiat Oncol Biol Phys 1996;34(4):867–872.PubMedGoogle Scholar
  103. 103.
    Cardillo TM, Blumenthal R, Ying Z, Gold DV. Combined gemcitabine and radioimmunotherapy for the treatment of pancreatic cancer. Int J Cancer 2002;97(3):386–392.PubMedGoogle Scholar
  104. 104.
    Lee NC, Bouvet M, Nardin S, Jiang P, Baranov E, Rashidi B, Yang M, Wang X, Moossa AR, Hoffma RM. Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model. Clin Exp Metastasis 2000;18(5):379–384.PubMedGoogle Scholar
  105. 105.
    Kelley JR, Fraser MM, Schweinfest CW, Vournakis JN, Watson DK, Cole DJ. CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer. Surgery 2001;130(2):280–288.PubMedGoogle Scholar
  106. 106.
    Haq M, Shafii A, Zervos EE, Rosemurgy AS. Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer. Cancer Res 2000;15;60(12):3207–3211.Google Scholar
  107. 107.
    Koshiba T, Hosotani R, Wada M, et al. Involvement of mat-rix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer 1998;82:642–650.PubMedGoogle Scholar
  108. 108.
    Bramhall SR, Neoptolemos JP, Stamp GW, Lemoine NR. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 1997;182:347–355.PubMedGoogle Scholar
  109. 109.
    Jimenez RE, Hartwig W, Antoniu BA, Compton CC, Warshaw AL, Fernandez-Del Castillo C. Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: an additive strategy for cancer control. Ann Surg 2000;231(5):644–654.PubMedGoogle Scholar
  110. 110.
    Matsushita A, Onda M, Uchida E, Maekawa R, Yoshioka T. Antitumor effect of a new selective matrix metalloproteinase inhibitor, MMI-166, on experimental pancreatic cancer. Int J Cancer 2001;92(3):434–440.PubMedGoogle Scholar
  111. 111.
    Bruns CJ, Harbison MT, Davis DW, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 2000;6(5):1936–1948.PubMedGoogle Scholar
  112. 112.
    Baker CH, Solorzano CC, Fidler IJ. Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res 2002;62(7):1996–2003.PubMedGoogle Scholar
  113. 113.
    Wei D, Le X, Zheng L, Wang L, Frey JA, et al. Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 2003;22(3):319–329.PubMedGoogle Scholar
  114. 114.
    Angeletti S, Corleto VD, Schillaci O, Moretti A, Panzuto F, Annibale B, Delle Fave G. Single dose of octreotide stabilize metastatic gastro-entero-pancreatic endocrine tumours. Ital J Gastroenterol Hepatol 1999;31(1):23–27.PubMedGoogle Scholar
  115. 115.
    Wenger FA, Kilian M, Braumann C, et al. Effects of taurolidine and octreotide on port site and liver metastasis after laparoscopy in an animal model of pancreatic cancer. Clin Exp Metastasis 2002;19(2):169–173.PubMedGoogle Scholar
  116. 116.
    Wenger FA, Kilian M, Jacobi CA, et al. Effects of octreotide on liver metastasis and intrametastatic lipid peroxidation in experimental pancreatic cancer. Oncology 2001;60(3):282–288.PubMedGoogle Scholar
  117. 117.
    Wenger FA, Kilian M, Mautsch I, et al. Influence of octreotide on liver metastasis and hepatic lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters. Pancreas 2001;23(3):266–272.PubMedGoogle Scholar
  118. 118.
    Gazdar AF, Minna JD. Targeted therapies for killing tumor cells. Proc Natl Acad Sci U S A 2001;98(18):10,028–10,030.Google Scholar
  119. 119.
    Gibbs JB, Oliff A, Kohl NE. Farnesyltransferase inhibitors: ras research yields a potential cancer therapeutic. Cell 1994;77:175–178.PubMedGoogle Scholar
  120. 120.
    Gibbs JB, Oliff A. Pharmaceutical research in molecular oncology. Cell 1994;79:193–198.PubMedGoogle Scholar
  121. 121.
    Sun J, Qian Y, Hamilton AD, Sebti SM. Ras CAAX peptido-mimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res 1995;55:4243–4247.PubMedGoogle Scholar
  122. 122.
    Takeuchi M, Shichinohe T, Senmaru N, et al. The dominant negative H-ras mutant, N116Y, suppresses growth of metastatic human pancreatic cancer cells in the liver of nude mice. Gene Ther 2000;7(6):518–526.PubMedGoogle Scholar
  123. 123.
    Su Z, Lebedeva IV, Gopalkrishnan RV, et al. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci U S A 2001;98(18):10,332–10,337.Google Scholar
  124. 124.
    Block A, Chen SH, Kosai K, Finegold M, Woo SL. Adenoviral-mediated herpes simplex virus thymidine kinase gene transfer: regression of hepatic metastasis of pancreatic tumors. Pancreas 1997;15(1):25–34.PubMedGoogle Scholar
  125. 125.
    Hwang RF, Gordon EM, Anderson WF, Parekh D. Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene. Surgery 1998;124(2):143–150.PubMedGoogle Scholar
  126. 126.
    Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH. Re ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 1997;3(6):639–645.PubMedGoogle Scholar
  127. 127.
    Bischoff JR, Kirn DH, Williams A, et al. An adenovirus mutant that replicates selec-tively in p53-deficient human tumor cells. Science 1996;274:373–376.PubMedGoogle Scholar
  128. 128.
    Freytag SO, Rogulski KR, Paielli DL, Gilbert JD, Kim JH. A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene and radiotherapy. Hum Gene Ther 1998;9:1323–1333.PubMedGoogle Scholar
  129. 129.
    Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol 2002;12(2):89–96.PubMedGoogle Scholar
  130. 130.
    Shi Q, Abbruzzese JL, Huang S, Ozawa S, Fidler IJ, and Xie K. Constitutive and Inducible Interleukin-8 Expression by Hypoxia and Acidosis Renders Human Pancreatic Cancer Cells More Tumorigenic and Metastatic. 2nd International Congress on Gastroenterological Carcinogenesis. March, 1999. Ulm, GermanyGoogle Scholar
  131. 131.
    Shi Q, Le X, Abbruzzese JL, et al. Cooperation between transcription factor AP-1 and NF-kB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia. J Interferon Cytokine Res 1999;19:1363–1271.PubMedGoogle Scholar
  132. 132.
    Shi Q, Le X, Wang B, Xiong Q, Abbruzzese JL, and Xie K. Regulation of interleukin-8 expression by cellular pH in human pancreatic adenocarcinoma cells. J Interferon Cytokine Res 2000;20:1544–1548.Google Scholar
  133. 133.
    Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J 1992;6:3051–3064.PubMedGoogle Scholar
  134. 134.
    Ambs S, Hussain SP, and Harris CC. Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J 1997;11:443–448.PubMedGoogle Scholar
  135. 135.
    Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB. The multifaceted roles of nitric oxide in cancer. Carcinogenesis 1998;19(5):711–721.PubMedGoogle Scholar
  136. 136.
    Xie K, and Fidler IJ. Therapy of cancer metastasis by activation of the inducible nitric oxide synthase. Cancer Metastasis Rev 1998;17(1):55–75.PubMedGoogle Scholar
  137. 137.
    Xie K, Bielenberg D, Huang S, et al. Abrogation of tumorigenicity and metastasis of murine and human tumor cells by transfection with the murine IFN-beta gene: possible role of nitric oxide. Clin Cancer Res 1997;3(12) Pt 1):2283–2294.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Daoyan Wei
    • 1
  • Henry Q. Xiong
    • 1
  • James L. Abbruzzese
    • 1
  • Keping Xie
    • 1
  1. 1.Department of Gastrointestinal Medical OncologyThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations