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Cell Signaling Pathways in Pancreatic Cancer

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Pancreatic Cancer

Part of the book series: M. D. Anderson Solid Tumor Oncology Series ((MDA))

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References

  1. Gudjonsson B. Cancer of the pancreas. 50 years of surgery. Cancer. 1987;60(9):2284–2303.

    CAS  PubMed  Google Scholar 

  2. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer. 1981;48(8):1705–1710.

    CAS  PubMed  Google Scholar 

  3. Cullinan SA, Moertel CG, Fleming TR, et al. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985;253(14):2061–2067.

    Article  CAS  PubMed  Google Scholar 

  4. Hruban RH, van Mansfeld AD, Offerhaus GJ et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143(2):545–554.

    CAS  PubMed  Google Scholar 

  5. Kalthoff H, Schmiegel W, Roeder C, et al. p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene. 1993;8(2):289–298.

    CAS  PubMed  Google Scholar 

  6. Pellegata NS, Sessa F, Renault B, et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res. 1949;4(6):1556–1560.

    Google Scholar 

  7. Lemoine NR, Jain S, Hughes CM, et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology. 1992;102(1):230–236.

    CAS  PubMed  Google Scholar 

  8. Villanueva A, Garcia C, Paules AB, et al. Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene. 1998;17(15):1969–1978.

    Article  CAS  PubMed  Google Scholar 

  9. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54(11):3025–3033.

    CAS  PubMed  Google Scholar 

  10. Schutte M, Hruban RH, Hedrick L, et al. DPC4 gene in various tumor types. Cancer Res. 1996;56(11):2527–2530.

    CAS  PubMed  Google Scholar 

  11. Rozenblum E, Schutte M, Goggins M, et al. Tumorsuppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57(9):1731–1734.

    CAS  PubMed  Google Scholar 

  12. Barton CM, Hall PA, Hughes CM, Gullick WJ, Lemoine NR. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J. Pathol. 1991;163(2):111–116.

    Article  CAS  PubMed  Google Scholar 

  13. Hall PA, Hughes CM, Staddon SL, Richman PI, Gullick WJ, Lemoine NR. The c-erb B-2 protooncogene in human pancreatic cancer. J Pathol. 1990;161(3):195–200.

    Article  CAS  PubMed  Google Scholar 

  14. Evans VG. Multiple pathways to apoptosis. Cell Biol Int. 1993;17(5):461–476.

    Article  CAS  PubMed  Google Scholar 

  15. Kraus MH, Pierce JH, Fleming TP, Robbins KC, Di Fiore PP, Aaronson SA. Mechanisms by which genes encoding growth factors and growth factor receptors contribute to malignant transformation. Ann N Y Acad Sci. 1988;551:320–335; discussion 336.

    CAS  PubMed  Google Scholar 

  16. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61(2):203–212.

    Article  CAS  PubMed  Google Scholar 

  17. Lemoine NR, Hall PA. Growth factors and oncogenes in pancreatic cancer. Baillieres Clin Gastroenterol. 1990;4(4):815–832.

    Article  CAS  PubMed  Google Scholar 

  18. Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M, Friess H. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res. 1995;1(11):1413–1420.

    CAS  PubMed  Google Scholar 

  19. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res. 1993;13(3):565–569.

    CAS  PubMed  Google Scholar 

  20. Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchier M, Beger HG. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest. 1992;90(4):1352–1360.

    CAS  PubMed  Google Scholar 

  21. Friess H, Berberat P, Schilling M, Kunz J, Korc M, Buchler WM. Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J Mol Med. 1996;74(1):35–42.

    Article  CAS  PubMed  Google Scholar 

  22. Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science. 1986;232(4758):1644–1646.

    CAS  PubMed  Google Scholar 

  23. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–712.

    CAS  PubMed  Google Scholar 

  24. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–182.

    CAS  PubMed  Google Scholar 

  25. Day JD, Digiuseppe JA, Yeo C, et al. Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol. 1996;27(2):119–124.

    CAS  PubMed  Google Scholar 

  26. Yamanaka Y, Friess H, Kobrin MS, et al. Overexpression of HER2/neu oncogene in human pancreatic carcinoma. Hum Pathol. 1993;24(10):1127–1134.

    Article  CAS  PubMed  Google Scholar 

  27. Naldini L, Weidner KM, Vigna E, et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991;10(10):2867–2878.

    CAS  PubMed  Google Scholar 

  28. Weidner KM, Sachs M, Birchmeier W. The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 1993;121(1):145–154.

    Article  CAS  PubMed  Google Scholar 

  29. Weidner KM, Behrens J, Vandekerckhove J, Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol. 1990;111:2097–2108.

    Article  CAS  PubMed  Google Scholar 

  30. Bussolino F, Di Renzo MF, Ziche M, et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol. 1992;119(3):629–641.

    Article  CAS  PubMed  Google Scholar 

  31. Hartmann G, Weidner KM, Schwarz H, Birchmeier W. The motility signal of scatter factor/hepatocyte growth factor mediated through the receptor tyrosine kinase met requires intracellular action of Ras. J Biol Chem. 1994;269(35):21936–21939.

    CAS  PubMed  Google Scholar 

  32. Ebert M, Yokoyama M, Friess H, Buchler MW, Korc M. Coexpression of the c-met protooncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res. 1994;54(22):5775–5778.

    CAS  PubMed  Google Scholar 

  33. Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 1995;55(5):1129–1138.

    PubMed  Google Scholar 

  34. Furukawa T, Duguid WP, Kobari M, Matsuno S, Tsao MS. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am J Pathol. 1995;147(4):889–895.

    CAS  PubMed  Google Scholar 

  35. Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753–791.

    Article  CAS  PubMed  Google Scholar 

  36. Massague J, Cheifetz S, Laiho M, Ralph DA, Weis FM, Zentella A. Transforming growth factor-beta. Cancer Surv. 1992;12:81–103.

    CAS  PubMed  Google Scholar 

  37. Polyak, K. Negative regulation of cell growth by TGF beta. Biochim Biophys Acta. 1996;1242(3):185–199.

    PubMed  Google Scholar 

  38. Markowitz SD, Roberts AB. Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev. 1996;7(1):93–102.

    Article  CAS  PubMed  Google Scholar 

  39. Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268(5215):1336–1338.

    CAS  PubMed  Google Scholar 

  40. Baldwin RL, Korc M. Growth inhibition of human pancreatic carcinoma cells by transforming growth factor beta-1. Growth Factors. 1993;8(1):23–34.

    CAS  PubMed  Google Scholar 

  41. Lu Z, Friess H, Graber HU, et al. Presence of two signaling TGF-beta receptors in human pancreatic cancer correlates with advanced tumor stage. Dig Dis Sci. 1997;42(10):2054–2063.

    Article  CAS  PubMed  Google Scholar 

  42. Friess H, Yamanaka Y, Buchler M, et al. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 1993;53(12):2704–2707.

    CAS  PubMed  Google Scholar 

  43. Wess J. G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J. 1997;11(5):346–354.

    CAS  PubMed  Google Scholar 

  44. Bourne HR. How receptors talk to trimeric G proteins. Curr Opin Cell Biol. 1997;9(2):134–142.

    Article  CAS  PubMed  Google Scholar 

  45. Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–891.

    Article  CAS  PubMed  Google Scholar 

  46. McCormick F. ras GTPase activating protein: signal transmitter and signal terminator. Cell. 1989;56(1):5–8.

    Article  CAS  PubMed  Google Scholar 

  47. Bos JL. The ras gene family and human carcinogenesis. Mutat Res. 1998;195(3):255–271.

    Google Scholar 

  48. Barbacid M. ras genes. Annu Rev Biochem. 1987;56:779–827.

    Article  CAS  PubMed  Google Scholar 

  49. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein ras regulates growth factor-induced membrane ruffling. Cell. 1992;70(3):401–410.

    CAS  PubMed  Google Scholar 

  50. Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992;70(3):389–399.

    CAS  PubMed  Google Scholar 

  51. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53(4):549–554.

    Article  CAS  PubMed  Google Scholar 

  52. Caldas C, Kern SE. K-ras mutation and pancreatic adenocarcinoma. Int J Pancreatol. 1995;18(1):1–6.

    CAS  PubMed  Google Scholar 

  53. Flanders TY, Foulkes WD. Pancreatic adenocarcinoma: epidemiology and genetics. J Med Genet. 1996;33(11):889–898.

    CAS  PubMed  Google Scholar 

  54. Rivera JA, Rall CJ, Graeme-Cook F, et al. Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia. Surgery. 1997;121(1):42–49.

    Article  CAS  PubMed  Google Scholar 

  55. Dergham ST, Dugan MC, Sarkar FH, Vaitkevicius VK. Molecular alterations associated with improved survival in pancreatic cancer patients treated with radiation or chemotherapy. J Hepatobiliary Pancreat Surg. 1998;5(3):269–272.

    Article  CAS  PubMed  Google Scholar 

  56. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994;8(2):133–146.

    CAS  PubMed  Google Scholar 

  57. Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics. 1995;139(3):1347–1358.

    CAS  PubMed  Google Scholar 

  58. Savage C, Das P, Finelli AL, Townsend SR, Sun CY, Baird SE, Padgett RW. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components. Proc Natl Acad Sci U S A. 1996;93(2):790–794.

    Article  CAS  PubMed  Google Scholar 

  59. Heldin CH, Johnsson A, Wennergren S, Wernstedt C, Betsholtz C, Westermark B. A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains. Nature. 1986;319(6053):511–514.

    Article  CAS  PubMed  Google Scholar 

  60. Liu F, Hata A, Baker JC, et al. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature. 1996;381(6583):620–623.

    Article  CAS  PubMed  Google Scholar 

  61. Kretzschmar M, Liu F, Hata A, Doody J, Massague J. The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev. 1997;11(8):984–995.

    CAS  PubMed  Google Scholar 

  62. Nishimura R, Kato Y, Chen D, Harris SE, Mundy GR, Yoneda T. Smad5 and DPC4 are key molecules in mediating BMP-2-induced osteoblastic differentiation of the pluripotent mesenchymal precursor cell line C2C12. J Biol Chem. 1998;273(4):1872–1879.

    Article  CAS  PubMed  Google Scholar 

  63. Chen Y, Bhushan A, Vale W. Smad8 mediates the signaling of the ALK-2 [corrected] receptor serine kinase. Proc Natl Acad Sci U S A. 1997;94(24):12938–12943.

    Article  CAS  PubMed  Google Scholar 

  64. Eppert K, Scherer SW, Ozcelik H, et al. MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell. 1996;86(4):543–552.

    Article  CAS  PubMed  Google Scholar 

  65. Zhang Y, Feng X, We R, Derynck R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature. 1996;383(6596):168–172.

    Article  CAS  PubMed  Google Scholar 

  66. Macias-Silva M, Abdollah S, Hoodless PA, Pirone R, Attisano L, Wrana JL. MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell. 1996;87(7):1215–1224.

    CAS  PubMed  Google Scholar 

  67. Lagna G, Hata A, Hemmati-Brivanlou A, Massague J. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature. 1996;383(6603):832–836.

    Article  CAS  PubMed  Google Scholar 

  68. Liu F, Pouponnot C, Massague J. Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes. Genes Dev. 1997;11(23):3157–3167.

    CAS  PubMed  Google Scholar 

  69. Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature. 1997;389(6646):85–89.

    Article  CAS  PubMed  Google Scholar 

  70. Topper JN, DiChiara MR, Brown JD, et al. CREB binding protein is a required coactivator for Smaddependent, transforming growth factor beta transcriptional responses in endothelial cells. Proc Natl Acad Sci U S A. 1998;95(16):9506–9511.

    Article  CAS  PubMed  Google Scholar 

  71. Hata A, Lagna G, Massague J, Hemmati-Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998;12(2):186–197.

    CAS  PubMed  Google Scholar 

  72. Hayashi H, Abdollah S, Qiu Y, et al. The MADrelated protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997;89(7):1165–1173.

    Article  CAS  PubMed  Google Scholar 

  73. Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997;389(6651):631–635.

    CAS  PubMed  Google Scholar 

  74. Tsuneizumi K, Nakayama T, Kamoshida Y, Kornberg TB, Christian JL, Tabata T. Daughters against dpp modulates dpp organizing activity in rosophila wing development. Nature. 1997;389(6651):627–631.

    CAS  PubMed  Google Scholar 

  75. Border WA, Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest. 1992;90(1):1–7.

    CAS  PubMed  Google Scholar 

  76. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271(5247):350–353.

    CAS  PubMed  Google Scholar 

  77. Hahn SA, Hoque AT, Moskaluk CA, et al. Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res. 1996;56(3):490–494.

    CAS  PubMed  Google Scholar 

  78. Shi Y, Hata A, Lo RS, Massague J, Pavletich NP. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997;388(6637):87–93.

    CAS  PubMed  Google Scholar 

  79. Grau AM, Zhang L, Wang W, et al. Induction of p21waf1 expression and growth inhibition by transforming growth factor beta involve the tumor suppressor gene DPC4 in human pancreatic adenocarcinoma cells. Cancer Res. 1997;57(18):3929–3394.

    CAS  PubMed  Google Scholar 

  80. Hunt K, Fleming J, Abramian A, Zhang L, Evans D, Chaio P. Overexpression of the tumor suppressor gene Smad4/DPC4 induces p21waf1 expression and growth inhibition in human carcinoma cells. Cancer Res. 1998;58:5656–5661.

    CAS  PubMed  Google Scholar 

  81. Chiao PJ, Hunt KK, Grau AM, Abramian A, Fleming J, Zhang W, Breslin T, Abbruzzese JL, Evans DB. Tumor suppressor gene Smad4/DPC4, its downstream target genes, and regulation of cell cycle. Ann N Y Acad Sci. 1999;880:21–37.

    Article  Google Scholar 

  82. Evan G, Littlewood T. A matter of life and cell death. Science 1988;281(5381):1317–1322.

    Google Scholar 

  83. Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672–1677.

    Article  CAS  PubMed  Google Scholar 

  84. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev. 1998;12(15):2245–2262.

    CAS  PubMed  Google Scholar 

  85. Adams PD, Kaelin WG Jr. Negative control elements of the cell cycle in human tumors. Curr Opin Cell Biol. 1998;10(6):791–797.

    Article  CAS  PubMed  Google Scholar 

  86. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366(6456):704–707.

    Article  CAS  PubMed  Google Scholar 

  87. Naumann M, Savitskaia N, Eilert C, Schramm A, Kalthoff H, Schmiegel W. Frequent codeletion of p16/MTS1 and p15/MTS2 and genetic alterations in p16/MTS1 in pancreatic tumors. Gastroenterology. 1996;110(4):1215–1224.

    Article  CAS  PubMed  Google Scholar 

  88. Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  89. Liu Q, Yan YX, McClure M, Nakagawa H, Fujimura F, Rustgi AK. MTS-1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagus squamous cancer and pancreatic adenocarcinoma cell lines. Oncogene. 1995;10(3):619–622.

    CAS  PubMed  Google Scholar 

  90. Huang L, Goodrow TL, Zhang SY, Klein-Szanto AJ, Chang H, Ruggeri BA. Deletion and mutation analyses of the P16/MTS-1 tumor suppressor gene in human ductal pancreatic cancer reveals a higher frequency of abnormalities in tumor-derived cell lines than in primary ductal adenocarcinomas. Cancer Res. 1996;56(5):1137–1141.

    CAS  PubMed  Google Scholar 

  91. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126–3130.

    CAS  PubMed  Google Scholar 

  92. Hall PA, Meek D, Lane DP. p53—integrating the complexity. J Pathol. 1996;180(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  93. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387(6630):296–299.

    Article  CAS  PubMed  Google Scholar 

  94. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability of Mdm2. Nature. 1997;387(6630):299–303.

    Article  CAS  PubMed  Google Scholar 

  95. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7A):1126–1132.

    CAS  PubMed  Google Scholar 

  96. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–331.

    Article  CAS  PubMed  Google Scholar 

  97. Scarpa A, Capelli P, Mukai K, et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol. 1993;142(5):1534–1543.

    CAS  PubMed  Google Scholar 

  98. Boschman CR, Stryker S, Reddy JK, Rao MS. Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am J Pathol. 1994;145(6):1291–1295.

    CAS  PubMed  Google Scholar 

  99. Ruggeri BA, Huang L, Berger D, et al. Molecular pathology of primary and metastic ductal pancreatic lesions: analyses of mutations and expression of the p53, mdm-2, and p21/WAF-1 genes in sporadic and familial lesions. Cancer. 1997;79(4):700–716.

    Article  CAS  PubMed  Google Scholar 

  100. Barton CM, Staddon SL, Hughes CM, et al. Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer. 1991;64(6):1076–1082.

    CAS  PubMed  Google Scholar 

  101. Ng CE, Banerjee SK, Pavliv M, Wang G, Raaphorst GP, Aubin RA. p53 status, cellular recovery and cell cycle arrest as prognosticators of in vitro radiosensitivity in human pancreatic adenocarcinoma cell lines. Int J Radiat Biol. 1999;75(11):1365–1376.

    CAS  PubMed  Google Scholar 

  102. Yokoyama M, Yamanaka Y, Friess H, Buchler M, Korc M. p53 expression in human pancreatic cancer correlates with enhanced biological aggressiveness. Anticancer Res. 1994;14(6B):2477–2483.

    CAS  PubMed  Google Scholar 

  103. Bold RJ, Hess KR, Pearson AS, et al. Prognostic factors in resectable pancreatic cancer: p53 and Bcl-2. J Gastrointest Surg. 1999;3(3):263–277.

    CAS  PubMed  Google Scholar 

  104. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371(6494):257–261.

    Article  CAS  PubMed  Google Scholar 

  105. Reynisdottir I, Massague J. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 1997;11(4):492–503.

    CAS  PubMed  Google Scholar 

  106. Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 1998;58:5329–5332.

    CAS  PubMed  Google Scholar 

  107. Suardet L, Little JB. Potential role of WAF1/Cip1 /p21 as a mediator of TGF-beta cytoinhibitory effect. Int. J Cancer. 1996;68(1):126–131.

    Article  CAS  PubMed  Google Scholar 

  108. Hahn SA, Seymour AB, Hoque AT, et al. Allelo-type of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res. 1995;55(20):4670–4675.

    CAS  PubMed  Google Scholar 

  109. Reyes G, Villaneuva A, Garcia C, et al. Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. Cancer Res. 1996;56(24):5713–5719.

    CAS  PubMed  Google Scholar 

  110. Bates S, Phillips AC, Clark PA, et al. p14ARF links the tumour suppressors RB and p53. Nature. 1998;395(6698):124–125.

    Article  CAS  PubMed  Google Scholar 

  111. Palmero I, Pantoja C, Serrano M. p19ARF links the tumour suppressor p53 to Ras. Nature. 1998;395(6698):125–126.

    Article  CAS  PubMed  Google Scholar 

  112. de Stanchina E, McCurrach ME, Zindy F, et al. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 1998;12(15):2434–2442.

    PubMed  Google Scholar 

  113. Zindy F, Eischen CM, Randle DH, et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 1998;12(15):2424–2433.

    CAS  PubMed  Google Scholar 

  114. Sharpless NE, DePinho RA. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev. 1999;9(1):22–30.

    Article  CAS  PubMed  Google Scholar 

  115. Honda R, Yasuda H. Association of p19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J. 1999;18(1):22–27.

    Article  CAS  PubMed  Google Scholar 

  116. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A. 1998;95(14):8292–8297.

    Article  CAS  PubMed  Google Scholar 

  117. Schwartz SA, Shuler CF, Freebeck P. Transformation of normal homologous cells by a spontaneously activated Ha-ras oncogene. Cancer Res. 1988;48(12):3470–3477.

    CAS  PubMed  Google Scholar 

  118. Houck KA, Michalopoulos GK, Strom SC. Introduction of a Ha-ras oncogene into rat liver epithelial cells and parenchymal hepatocytes confers resistance to the growth inhibitory effects of TGF-beta. Oncogene. 1989;4(1):19–25.

    CAS  PubMed  Google Scholar 

  119. Filmus J, Kerbel RS. Development of resistance mechanisms to the growth-inhibitory effects of transforming growth factor-beta during tumor progression. Curr Opin Oncol. 1993;5(1):123–129.

    CAS  PubMed  Google Scholar 

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Authors
  1. Jason B. Fleming
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Editors and Affiliations

  1. Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Douglas B. Evans M.D. (Professor of Surgery) & Peter W. T. Pisters M.D., F.A.C.S. (Associate Professor of Surgery) (Professor of Surgery) &  (Associate Professor of Surgery)

  2. Department of Gastrointestinal Medical Oncology, The University Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    James L. Abbruzzese M.D. (Professor of Medical Oncology, Chairman) (Professor of Medical Oncology, Chairman)

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© 2002 Springer-Verlag New York, Inc.

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Fleming, J.B. (2002). Cell Signaling Pathways in Pancreatic Cancer. In: Evans, D.B., Pisters, P.W.T., Abbruzzese, J.L. (eds) Pancreatic Cancer. M. D. Anderson Solid Tumor Oncology Series. Springer, New York, NY. https://doi.org/10.1007/0-387-21600-6_4

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  • DOI: https://doi.org/10.1007/0-387-21600-6_4

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-0-387-95185-0

  • Online ISBN: 978-0-387-21600-3

  • eBook Packages: Springer Book Archive

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