Genetics and biology of pancreatic ductal adenocarcinoma

Genes and Development

Volumn 20, Issue 10, 2006, Pages 1218-1249

  Hezel, Aram F ^a   Kimmelman, Alec C ^a,b   Stanger, Ben Z ^b   Bardeesy, Nabeel ^c   DePinho, Ronald A ^a,b,d  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b MASSACHUSETTS GENERAL HOSPITAL   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER   (United States)

^d HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Genetics; Genomic stem cell; Mouse models; Pancreas; Pancreatic cancer

Indexed keywords

ARF PROTEIN; EPIDERMAL GROWTH FACTOR; FIBROBLAST GROWTH FACTOR; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; NOTCH RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE LKB1; PROTEIN P53; PROTEIN SERINE THREONINE KINASE; SCATTER FACTOR; SCATTER FACTOR RECEPTOR; SMAD4 PROTEIN; SOMATOMEDIN; SONIC HEDGEHOG PROTEIN; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN;

ACINAR CELL; ACINAR CELL CARCINOMA; CANCER DIAGNOSIS; CANCER GENETICS; CANCER GROWTH; CANCER MORTALITY; CANCER RESEARCH; CANCER STEM CELL; CANCER SURVIVAL; CARCINOGENESIS; CHROMOSOME 9P; CLINICAL FEATURE; DISEASE RESISTANCE; HISTOPATHOLOGY; HUMAN; METASTASIS; MOLECULAR GENETICS; MUTATION; NONHUMAN; ONCOGENE K RAS; PANCREAS ADENOCARCINOMA; PANCREAS DUCT; PREVALENCE; PRIORITY JOURNAL; REVIEW; SURVIVAL RATE; TELOMERE; TUMOR SUPPRESSOR GENE; UNITED STATES;

ANIMALS; CARCINOMA, PANCREATIC DUCTAL; DISEASE MODELS, ANIMAL; HUMANS; MICE; MICE, MUTANT STRAINS; PANCREAS; PANCREATIC NEOPLASMS;

EID: 33646577163     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.1415606     Document Type: Review

References (382)

1. Abraham, S.C., Wu, T.T., Klimstra, D.S., Finn, L.S., Lee, J.H., Yeo, C.J., Cameron, J.L., and Hruban, R.H. 2001. Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: Frequent alterations in the APC/β-catenin pathway and chromosome 11p. Am. J. Pathol. 159: 1619-1627.
2. Adsay, N.V., Merati, K., Basturk, O., Iacobuzio-Donahue, C., Levi, E., Cheng, J.D., Sarkar, F.H., Hruban, R.H., and Klimstra, D.S. 2004. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: Delineation of an 'intestinal' pathway of carcinogenesis in the pancreas. Am. J. Surg. Pathol. 28: 839-848.
3. Agbunag, C. and Bar-Sagi, D. 2004. Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells. Cancer Res. 64: 5659-5663.
4. Aguirre, A.J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D.A., Horner, J., Redston, M.S., and DePinho, R.A. 2003. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes & Dev. 17: 3112-3126.
5. Aguirre, A.J., Brennan, C., Bailey, G., Sinha, R., Feng, B., Leo, C., Zhang, Y., Zhang, J., Gans, J.D., Bardeesy, N., et al. 2004. High-resolution characterization of the pancreatic adenocarcinoma genome. Proc. Natl. Acad. Sci. 101: 9067-9072.
6. Akhurst, R.J. and Derynck, R. 2001. TGF-β signaling in cancer - A double-edged sword. Trends Cell Biol. 11: S44-S51.
7. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., and Clarke, M.F. 2003. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. 100: 3983-3988.
8. Almoguera, C., Shibata, D., Forrester, K., Martin, J., Arnheim, N., and Perucho, M. 1988. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53: 549-554.
9. Altomare, D.A., Tanno, S., De Rienzo, A., Klein-Szanto, A.J., Tanno, S., Skele, K.L., Hoffman, J.P., and Testa, J.R. 2003. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J. Cell. Biochem. 88: 470-476.
10. Apelqvist, A., Ahlgren, U., and Edlund, H. 1997. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr. Biol. 7: 801-804.
11. Apelqvist, A., Li, H., Sommer, L., Beatus, P., Anderson, D.J., Honjo, T., Hrabe de Angelis, M., Lendahl, U., and Edlund, H. 1999. Notch signalling controls pancreatic cell differentiation. Nature 400: 877-881.
12. Argani, P., Rosty, C., Reiter, R.E., Wilentz, R.E., Murugesan, S.R., Leach, S.D., Ryu, B., Skinner, H.G., Goggins, M., Jaffee, E.M., et al. 2001. Discovery of new markers of cancer through serial analysis of gene expression: Prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res. 61: 4320-4324.
13. Arlt, A., Gehrz, A., Muerkoster, S., Vorndamm, J., Kruse, M.L., Folsch, U.R., and Schafer, H. 2003. Role of NF-κB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 22: 3243-3251.
14. Armengol, G., Knuutila, S., Lluis, F., Capella, G., Miro, R., and Caballin, M.R. 2000. DNA copy number changes and evaluation of MYC, IGF1R, and FES amplification in xenografts of pancreatic adenocarcinoma. Cancer Genet. Cytogenet. 116: 133-141.
15. Arnush, M., Gu, D., Baugh, C., Sawyer, S.P., Mroczkowski, B., Krahl, T., and Sarvetnick, N. 1996. Growth factors in the regenerating pancreas of γ-interferon transgenic mice. Lab. Invest. 74: 985-990.
16. Arsura, M., Mercurio, F., Oliver, A.L., Thorgeirsson, S.S., and Sonenshein, G.E. 2000. Role of the IκB kinase complex in oncogenic Ras- and Raf-mediated transformation of rat liver epithelial cells. Mol. Cell. Biol. 20: 5381-5391.
17. Artandi, S.E., Chang, S., Lee, S.L., Alson, S., Gottlieb, G.J., Chin, L., and DePinho, R.A. 2000. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406: 641-645.
18. Asano, T., Yao, Y., Zhu, J., Li, D., Abbruzzese, J.L., and Reddy, S.A. 2004. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells. Oncogene 23: 8571-8580.
19. _. 2005. The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation. Biochem. Biophys. Res. Commun. 331: 295-302.
20. Baas, A.F., Kuipers, J., van der Wel, N.N., Batlle, E., Koerten, H.K., Peters, P.J., and Clevers, H.C. 2004. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116: 457-466.
21. Baccarini, M. 2005. Second nature: Biological functions of the Raf-1 'kinase.' FEBS Lett. 579: 3271-3277.
22. Bachoo, R.M., Maher, E.A., Ligon, K.L., Sharpless, N.E., Chan, S.S., You, M.J., Tang, Y., DeFrances, J., Stover, E., Weissleder, R., et al. 2002. Epidermal growth factor receptor and Ink4a/Arf. Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1: 269-277.
23. Bardeesy, N., Morgan, J., Sinha, M., Signoretti, S., Srivastava, S., Loda, M., Merlino, G., and DePinho, R.A. 2002a. Obligate roles for p16(Ink4a) and p19(Arf)-p53 in the suppression of murine pancreatic neoplasia. Mol. Cell. Biol. 22: 635-643.
24. Bardeesy, N., Sinha, M., Hezel, A.F., Signoretti, S., Hathaway, N.A., Sharpless, N.E., Loda, M., Carrasco, D.R., and DePinho, R.A. 2002b. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419: 162-167.
25. Bardeesy, N., Kim, M., Xu, J., Kim, R.S., Shen, Q., Bosenberg, M.W., Wong, W.H., and Chin, L. 2005. Role of epidermal growth factor receptor signaling in RAS-driven melanoma. Mol. Cell. Biol. 25: 4176-4188.
26. Bardeesy, N., Aguirre, A., Chu, G., Cheng, K., Lopez, L., Hezel, A.F., Feng, B., Brennan, C., Weissleder, R., Mahmood, U., et al. 2006. Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl. Acad. Sci. 103: 5947-5952.
27. Barton, C.M., Hall, P.A., Hughes, C.M., Gullick, W.J., and Lemoine, N.R. 1991. Transforming growth factor α and epidermal growth factor in human pancreatic cancer. J. Pathol. 163: 111-116.
28. Bashyam, M.D., Bair, R., Kim, Y.H., Wang, P., Hernandez-Boussard, T., Karikari, C.A., Tibshirani, R., Maitra, A., and Pollack, J.R. 2005. Array-based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer. Neoplasia 7: 556-562.
29. Beachy, P.A., Karhadkar, S.S., and Berman, D.M. 2004. Tissue repair and stem cell renewal in carcinogenesis. Nature 432: 324-331.
30. Beausejour, C.M., Krtolica, A., Galimi, F., Narita, M., Lowe, S.W., Yaswen, P., and Campisi, J. 2003. Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J. 22: 4212-4222.
31. Benanti, J.A. and Galloway, D.A. 2004. Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol. 24: 2842-2852.
32. Bergmann, U., Funatomi, H., Yokoyama, M., Beger, H.G., and Korc, M. 1995. Insulin-like growth factor I overexpression in human pancreatic cancer: Evidence for autocrine and paracrine roles. Cancer Res. 55: 2007-2011.
33. Berman, D.M., Karhadkar, S.S., Maitra, A., Montes De Oca, R., Gerstenblith, M.R., Briggs, K., Parker, A.R., Shimada, Y., Eshleman, J.R., Watkins, D.N., et al. 2003. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425: 846-851.
34. Berrington de Gonzalez, A., Sweetland, S., and Spencer, E. 2003. A meta-analysis of obesity and the risk of pancreatic cancer. Br. J. Cancer 89: 519-523.
35. Bharti, A.C. and Aggarwal, B.B. 2002. Nuclear factor-κ B and cancer: Its role in prevention and therapy. Biochem. Pharmacol. 64: 883-888.
36. Biankin, A.V., Morey, A.L., Lee, C.S., Kench, J.G., Biankin, S.A., Hook, H.C., Head, D.R., Hugh, T.B., Sutherland, R.L., and Henshall, S.M. 2002. DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J. Clin. Oncol. 20: 4531-4542.
37. Blau, H.M., Brazelton, T.R., and Weimann, J.M. 2001. The evolving concept of a stem cell: Entity or function? Cell 105: 829-841.
38. Bonner-Weir, S. and Sharma, A. 2002. Pancreatic stem cells. J. Pathol. 197: 519-526.
39. Bonner-Weir, S., Stubbs, M., Reitz, P., Taneja, M., and Smith, F.E. 1997. Partial pancreatectomy as a model of pancreatic regeneration. In Pancreatic growth and regeneration (ed. N. Sarvetnick), pp. 138-153. Karger Landes Systems, Basel, Switzerland.
40. Bonnet, D. and Dick, J.E. 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3: 730-737.
41. Borg, A., Sandberg, T., Nilsson, K., Johannsson, O., Klinker, M., Masback, A., Westerdahl, J., Olsson, H., and Ingvar, C. 2000. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl. Cancer Inst. 92: 1260-1266.
42. Boschman, C.R., Stryker, S., Reddy, J.K., and Rao, M.S. 1994. Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am. J. Pathol. 145: 1291-1295.
43. Brembeck, F.H., Schreiber, F.S., Deramaudt, T.B., Craig, L., Rhoades, B., Swain, G., Grippo, P., Stoffers, D.A., Silberg, D.G., and Rustgi, A.K. 2003. The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res. 63: 2005-2009.
44. Brookes, S., Rowe, J., Ruas, M., Llanos, S., Clark, P.A., Lomax, M., James, M.C., Vatcheva, R., Bates, S., Vousden, K.H., et al. 2002. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J. 21: 2936-2945.
45. Brookes, S., Rowe, J., Gutierrez Del Arroyo, A., Bond, J., and Peters, G. 2004. Contribution of p16(INK4a) to replicative senescence of human fibroblasts. Exp. Cell Res. 298: 549-559.
46. Brugge, W.R., Lauwers, G.Y., Sahani, D., Fernandez-del Castillo, C., and Warshaw, A.L. 2004. Cystic neoplasms of the pancreas. N. Engl. J. Med. 351: 1218-1226.
47. Brummelkamp, T.R., Bernards, R., and Agami, R. 2002. A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550-553.
48. Bruns, C.J., Solorzano, C.C., Harbison, M.T., Ozawa, S., Tsan, R., Fan, D., Abbruzzese, J., Traxler, P., Buchdunger, E., Radinsky, R., et al. 2000. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res. 60: 2926-2935.
49. Bruns, C.J., Koehl, G.E., Guba, M., Yezhelyev, M., Steinbauer, M., Seeliger, H., Schwend, A., Hoehn, A., Jauch, K.W., and Geissler, E.K. 2004. Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin. Cancer Res. 10: 2109-2119.
50. Calhoun, E.S., Jones, J.B., Ashfaq, R., Adsay, V., Baker, S.J., Valentine, V., Hempen, P.M., Hilgers, W., Yeo, C.J., Hruban, R.H., et al. 2003. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: Potential therapeutic targets. Am. J. Pathol. 163: 1255-1260.
51. Camonis, J.H. and White, M.A. 2005. Ral GTPases: Corrupting the exocyst in cancer cells. Trends Cell Biol. 15: 327-332.
52. Campbell, S.L., Khosravi-Far, R., Rossman, K.L., Clark, G.J., and Der, C.J. 1998. Increasing complexity of Ras signaling. Oncogene 17: 1395-1413.
53. Cantley, L.C. 2002. The phosphoinositide 3-kinase pathway. Science 296: 1655-1657.
54. Chandler, N.M., Canete, J.J., and Callery, M.P. 2004. Increased expression of NF-κ B subunits in human pancreatic cancer cells. J. Surg. Res. 118: 9-14.
55. Cheng, J.Q., Ruggeri, B., Klein, W.M., Sonoda, G., Altomare, D.A., Watson, D.K., and Testa, J.R. 1996. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. 93: 3636-3641.
56. Chien, Y. and White, M.A. 2003. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 4: 800-806.
57. Chin, L., Pomerantz, J., Polsky, D., Jacobson, M., Cohen, C., Cordon-Cardo, C., Horner II, J.W., and DePinho, R.A. 1997. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes & Dev. 11: 2822-2834.
58. Chin, L., Artandi, S.E., Shen, Q., Tam, A., Lee, S.L., Gottlieb, G.J., Greider, C.W., and DePinho, R.A. 1999a. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97: 527-538.
59. Chin, L., Tam, A., Pomerantz, J., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., et al. 1999b. Essential role for oncogenic Ras in tumour maintenance. Nature 400: 468-472.
60. Chin, K., de Solorzano, C.O., Knowles, D., Jones, A., Chou, W., Rodriguez, E.G., Kuo, W.L., Ljung, B.M., Chew, K., Myambo, K., et al. 2004. In situ analyses of genome instability in breast cancer. Nat. Genet. 36: 984-988.
61. Cimini, D. and Degrassi, F. 2005. Aneuploidy: A matter of bad connections. Trends Cell Biol. 15: 442-451.
62. Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A.J., Barradas, M., Benguria, A., Zaballos, A., Flores, J.M., Barbacid, M., et al. 2005. Tumour biology: Senescence in premalignant tumours. Nature 436: 642.
63. Collins, C.J. and Sedivy, J.M. 2003. Involvement of the INK4a/Arf gene locus in senescence. Aging Cell 2: 145-150.
64. Collins, A.T., Berry, P.A., Hyde, C., Stower, M.J., and Maitland, N.J. 2005. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65: 10946-10951.
65. Cooper, H.S. 1998. Benign epithelial polyps of the intestines. In Pathology of the gastrointestinal tract (eds. S.-C. Ming and H. Goldman), pp. 819-853. Wiliams & Wilkens, Baltimore.
66. Corradetti, M.N., Inoki, K., Bardeesy, N., DePinho, R.A., and Guan, K.L. 2004. Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes & Dev. 18: 1533-1538.
67. Corso, S., Comoglio, P.M., and Giordano, S. 2005. Cancer therapy: Can the challenge be MET? Trends Mol. Med. 11: 284-292.
68. Crnogorac-Jurcevic, T., Efthimiou, E., Nielsen, T., Loader, J., Terris, B., Stamp, G., Baron, A., Scarpa, A., and Lemoine, N.R. 2002. Expression profiling of microdissected pancreatic adenocarcinomas. Oncogene 21: 4587-4594.
69. Cross, M.J. and Claesson-Welsh, L. 2001. FGF and VEGF function in angiogenesis: Signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol. Sci. 22: 201-207.
70. Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M.J., Bottomley, W., et al. 2002. Mutations of the BRAF gene in human cancer. Nature 417: 949-954.
71. Dessimoz, J., Bonnard, C., Huelsken, J., and Grapin-Botton, A. 2005. Pancreas-specific deletion of β-catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr. Biol. 15: 1677-1683.
72. Di Renzo, M.F., Poulsom, R., Olivero, M., Comoglio, P.M., and Lemoine, N.R. 1995. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 55: 1129-1138.
73. Dong, Q.G., Sclabas, G.M., Fujioka, S., Schmidt, C., Peng, B., Wu, T., Tsao, M.S., Evans, D.B., Abbruzzese, J.L., McDonnell, T.J., et al. 2002. The function of multiple IκB: NF-κB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene 21: 6510-6519.
74. Dor, Y., Brown, J., Martinez, O.I., and Melton, D.A. 2004. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429: 41-46.
75. Drayton, S., Rowe, J., Jones, R., Vatcheva, R., Cuthbert-Heavens, D., Marshall, J., Fried, M., and Peters, G. 2003. Tumor suppressor p16INK4a determines sensitivity of human cells to transformation by cooperating cellular oncogenes. Cancer Cell 4: 301-310.
76. Duda, D.G., Sunamura, M., Lefter, L.P., Furukawa, T., Yokoyama, T., Yatsuoka, T., Abe, T., Inoue, H., Motoi, F., Egawa, S., et al. 2003. Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells. Oncogene 22: 6857-6864.
77. Duesberg, P. and Rasnick, D. 2000. Aneuploidy, the somatic mutation that makes cancer a species of its own. Cell Motil. Cytoskeleton 47: 81-107.
78. Eberle, M.A., Pfutzer, R., Pogue-Geile, K.L., Bronner, M.P., Crispin, D., Kimmey, M.B., Duerr, R.H., Kruglyak, L., Whitcomb, D.C., and Brentnall, T.A. 2002. A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34. Am. J. Hum. Genet. 70: 1044-1048.
79. Ebert, M., Yokoyama, M., Kobrin, M.S., Friess, H., Lopez, M.E., Buchler, M.W., Johnson, G.R., and Korc, M. 1994. Induction and expression of amphiregulin in human pancreatic cancer. Cancer Res. 54: 3959-3962.
80. Ellenrieder, V., Hendler, S.F., Boeck, W., Seufferlein, T., Menke, A., Ruhland, C., Adler, G., and Gress, T.M. 2001a. Transforming growth factor β1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 61: 4222-4228.
81. Ellenrieder, V., Hendler, S.F., Ruhland, C., Boeck, W., Adler, G., and Gress, T.M. 2001b. TGF-β-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int. J. Cancer 93: 204-211.
82. Elliott, R.L. and Blobe, G.C. 2005. Role of transforming growth factor β in human cancer. J. Clin. Oncol. 23: 2078-2093.
83. Esni, F., Ghosh, B., Biankin, A.V., Lin, J.W., Albert, M.A., Yu, X., MacDonald, R.J., Civin, C.I., Real, F.X., Pack, M.A., et al. 2004. Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131: 4213-4224.
84. Everhart, J. and Wright, D. 1995. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 273: 1605-1609.
85. Fang, D., Nguyen, T.K., Leishear, K., Finko, R., Kulp, A.N., Hotz, S., Van Belle, P.A., Xu, X., Elder, D.E., and Herlyn, M. 2005. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 65: 9328-9337.
86. Feig, L.A. 2003. Ral-GTPases: Approaching their 15 minutes of fame. Trends Cell Biol. 13: 419-425.
87. Fernandez-Zapico, M.E., Gonzalez-Paz, N.C., Weiss, E., Savoy, D.N., Molina, J.R., Fonseca, R., Smyrk, T.C., Chari, S.T., Urrutia, R., and Billadeau, D.D. 2005. Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell 7: 39-49.
88. Ferrara, N., Gerber, H.P., and LeCouter, J. 2003. The biology of VEGF and its receptors. Nat. Med. 9: 669-676.
89. Fidler, I.J. and Hart, I.R. 1982. Biological diversity in metastatic neoplasms: Origins and implications. Science 217: 998-1003.
90. Fisher, G.H., Wellen, S.L., Klimstra, D., Lenczowski, J.M., Tichelaar, J.W., Lizak, M.J., Whitsett, J.A., Koretsky, A., and Varmus, H.E. 2001. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes & Dev. 15: 3249-3262.
91. Fleming, J.B., Shen, G.L., Holloway, S.E., Davis, M., and Brekken, R.A. 2005. Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: Justification for K-ras-directed therapy. Mol. Cancer Res. 3: 413-423.
92. Friess, H., Yamanaka, Y., Buchler, M., Berger, H.G., Kobrin, M.S., Baldwin, R.L., and Korc, M. 1993. Enhanced expression of the type II transforming growth factor β receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 53: 2704-2707.
93. Friess, H., Yamanaka, Y., Kobrin, M.S., Do, D.A., Buchler, M.W., and Korc, M. 1995. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin. Cancer Res. 1: 1413-1420.
94. Friess, H., Berberat, P., Schilling, M., Kunz, J., Korc, M., and Buchler, M.W. 1996. Pancreatic cancer: The potential clinical relevance of alterations in growth factors and their receptors. J. Mol. Med. 74: 35-42.
95. Friess, H., Wang, L., Zhu, Z., Gerber, R., Schroder, M., Fukuda, A., Zimmermann, A., Korc, M., and Buchler, M.W. 1999. Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas. Ann. Surg. 230: 767-774; discussion 774-765.
96. Fuchs, C.S., Colditz, G.A., Stampfer, M.J., Giovannucci, E.L., Hunter, D.J., Rimm, E.B., Willett, W.C., and Speizer, F.E. 1996. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch. Intern. Med. 156: 2255-2260.
97. Fujioka, S., Sclabas, G.M., Schmidt, C., Frederick, W.A., Dong, Q.G., Abbruzzese, J.L., Evans, D.B., Baker, C., and Chiao, P.J. 2003. Function of nuclear factor κB in pancreatic cancer metastasis. Clin. Cancer Res. 9: 346-354.
98. Fukasawa, M. and Korc, M. 2004. Vascular endothelial growth factor-trap suppresses tumorigenicity of multiple pancreatic cancer cell lines. Clin. Cancer Res. 10: 3327-3332.
99. Furukawa, T., Duguid, W.P., Kobari, M., Matsuno, S., and Tsao, M.S. 1995. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am. J. Pathol. 147: 889-895.
100. Gapstur, S.M., Gann, P.H., Lowe, W., Liu, K., Colangelo, L., and Dyer, A. 2000. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 283: 2552-2558.
101. Garnett, M.J. and Marais, R. 2004. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6: 313-319.
102. Garraway, L.A., Widlund, H.R., Rubin, M.A., Getz, G., Berger, A.J., Ramaswamy, S., Beroukhim, R., Milner, D.A., Granter, S.R., Du, J., et al. 2005. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436: 117-122.
103. Ghosh, S., May, M.J., and Kopp, E.B. 1998. NF-κB and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16: 225-260.
104. Giardiello, F.M., Brensinger, J.D., Tersmette, A.C., Goodman, S.N., Petersen, G.M., Booker, S.V., Cruz-Correa, M., and Offerhaus, J.A. 2000. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119: 1447-1453.
105. Gisselsson, D., Jonson, T., Petersen, A., Strombeck, B., Dal Cin, P., Hoglund, M., Mitelman, F., Mertens, F., and Mandahl, N. 2001. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl. Acad. Sci. 98: 12683-12688.
106. Glasner, S., Memoli, V., and Longnecker, D.S. 1992. Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors. Am. J. Pathol. 140: 1237-1245.
107. Goggins, M., Hruban, R.H., and Kern, S.E. 2000. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: Evidence and implications. Am. J. Pathol. 156: 1767-1771.
108. Goldstein, A.M., Fraser, M.C., Struewing, J.P., Hussussian, C.J., Ranade, K., Zametkin, D.P., Fontaine, L.S., Organic, S.M., Dracopoli, N.C., Clark Jr., W.H., et al. 1995. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations [see comments]. N. Engl. J. Med. 333: 970-974.
109. Goldstein, A.M., Struewing, J.P., Chidambaram, A., Fraser, M.C., and Tucker, M.A. 2000. Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J. Natl. Cancer Inst. 92: 1006-1010.
110. Gomez del Pulgar, T., Benitah, S.A., Valeron, P.F., Espina, C., and Lacal, J.C. 2005. Rho GTPase expression in tumourigenesis: Evidence for a significant link. Bioessays 27: 602-613.
111. Gorunova, L., Hoglund, M., Andren-Sandberg, A., Dawiskiba, S., Jin, Y., Mitelman, F., and Johansson, B. 1998. Cytogenetic analysis of pancreatic carcinomas: Intratumor heterogeneity and nonrandom pattern of chromosome aberrations. Genes Chromosomes Cancer 23: 81-99.
112. Greenberg, R.A., Chin, L., Femino, A., Lee, K.H., Gottlieb, G.J., Singer, R.H., Greider, C.W., and DePinho, R.A. 1999. Short dysfunctional telomeres impair tumorigenesis in the INK4a(Δ2/3) cancer-prone mouse. Cell 97: 515-525.
113. Grippo, P.J., Nowlin, P.S., Demeure, M.J., Longnecker, D.S., and Sandgren, E.P. 2003. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 63: 2016-2019.
114. Grutzmann, R., Foerder, M., Alldinger, I., Staub, E., Brummendorf, T., Ropcke, S., Li, X., Kristiansen, G., Jesnowski, R., Sipos, B., et al. 2003. Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch. 443: 508-517.
115. Gu, G., Dubauskaite, J., and Melton, D.A. 2002. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129: 2447-2457.
116. Gu, G., Brown, J.R., and Melton, D.A. 2003. Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis. Mech. Dev. 120: 35-43.
117. Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., Campuzano, V., and Barbacid, M. 2003. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4: 111-120.
118. Gysin, S., Lee, S.H., Dean, N.M., and McMahon, M. 2005. Pharmacologic inhibition of RAF → MEK → ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res. 65: 4870-4880.
119. Hahn, S.A., Schutte, M., Hoque, A.T., Moskaluk, C.A., da Costa, L.T., Rozenblum, E., Weinstein, C.L., Fischer, A., Yeo, C.J., Hruban, R.H., et al. 1996. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 [see comments]. Science 271: 350-353.
120. Hahn, W.C., Counter, C.M., Lundberg, A.S., Beijersbergen, R.L., Brooks, M.W., and Weinberg, R.A. 1999. Creation of human tumour cells with defined genetic elements. Nature 400: 464-468.
121. Hald, J., Hjorth, J.P., German, M.S., Madsen, O.D., Serup, P., and Jensen, J. 2003. Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development. Dev. Biol. 260: 426-437.
122. Han, H., Bearss, D.J., Browne, L.W., Calaluce, R., Nagle, R.B., and Von Hoff, D.D. 2002. Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res. 62: 2890-2896.
123. Hanson, J.L., Hawke, N.A., Kashatus, D., and Baldwin, A.S. 2004. The nuclear factor κB subunits RelA/p65 and c-Rel potentiate but are not required for Ras-induced cellular transformation. Cancer Res. 64: 7248-7255.
124. Harada, T., Okita, K., Shiraishi, K., Kusano, N., Kondoh, S., and Sasaki, K. 2002. Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res. 62: 835-839.
125. Hardie, D.G. 2005. New roles for the LKB1 → AMPK pathway. Curr. Opin. Cell Biol. 17: 167-173.
126. Hart, A., Papadopoulou, S., and Edlund, H. 2003. Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells. Dev. Dyn. 228: 185-193.
127. Hayden, M.S. and Ghosh, S. 2004. Signaling to NF-κB. Genes & Dev. 18: 2195-2224.
128. Hebrok, M., Kim, S.K., and Melton, D.A. 1998. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes & Dev. 12: 1705-1713.
129. Heidenblad, M., Schoenmakers, E.F., Jonson, T., Gorunova, L., Veltman, J.A., van Kessel, A.G., and Hoglund, M. 2004. Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines. Cancer Res. 64: 3052-3059.
130. Heinmoller, E., Dietmaier, W., Zirngibl, H., Heinmoller, P., Scaringe, W., Jauch, K.W., Hofstadter, F., and Ruschoff, J. 2000. Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. Am. J. Pathol. 157: 83-92.
131. Hemminki, A., Markie, D., Tomlinson, I., Avizienyte, E., Roth, S., Loukola, A., Bignell, G., Warren, W., Aminoff, M., Hoglund, P., et al. 1998. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391: 184-187.
132. Heppner, G.H. 1984. Tumor heterogeneity. Cancer Res. 44: 2259-2265.
133. Herbig, U., Jobling, W.A., Chen, B.P., Chen, D.J., and Sedivy, J.M. 2004. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14: 501-513.
134. Hingorani, S.R., Petricoin, E.F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M.A., Ross, S., Conrads, T.P., Veenstra, T.D., Hitt, B.A., et al. 2003. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4: 437-450.
135. Hingorani, S.R., Wang, L., Multani, A.S., Combs, C., Deramaudt, T.B., Hruban, R.H., Rustgi, A.K., Chang, S., and Tuveson, D.A. 2005. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7: 469-483.
136. Hirano, T., Shino, Y., Saito, T., Komoda, F., Okutomi, Y., Takeda, A., Ishihara, T., Yamaguchi, T., Saisho, H., and Shirasawa, H. 2002. Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. Oncogene 21: 5923-5928.
137. Hogan, B.L. 1999. Morphogenesis. Cell 96: 225-233.
138. Holzmann, K., Kohlhammer, H., Schwaenen, C., Wessendorf, S., Kestler, H.A., Schwoerer, A., Rau, B., Radlwimmer, B., Dohner, H., Lichter, P., et al. 2004. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res. 64: 4428-4433.
139. Hoshida, T., Sunamura, M., Duda, D.G., Egawa, S., Miyazaki, S., Shineha, R., Hamada, H., Ohtani, H., Satomi, S., and Matsuno, S. 2002. Gene therapy for pancreatic cancer using an adenovirus vector encoding soluble flt-1 vascular endothelial growth factor receptor. Pancreas 25: 111-121.
140. Hotz, H.G., Hines, O.J., Hotz, B., Foitzik, T., Buhr, H.J., and Reber, H.A. 2003. Evaluation of vascular endothelial growth factor blockade and matrix metalloproteinase inhibition as a combination therapy for experimental human pancreatic cancer. J. Gastrointest. Surg. 7: 220-227; discussion 227-228.
141. Hruban, R.H., Goggins, M., Parsons, J., and Kern, S.E. 2000a. Progression model for pancreatic cancer. Clin. Cancer Res. 6: 2969-2972.
142. Hruban, R.H., Wilentz, R.E., and Kern, S.E. 2000b. Genetic progression in the pancreatic ducts. Am. J. Pathol. 156: 1821-1825.
143. Hruban, R.H., Adsay, N.V., Albores-Saavedra, J., Compton, C., Garrett, E.S., Goodman, S.N., Kern, S.E., Klimstra, D.S., Kloppel, G., Longnecker, D.S., et al. 2001. Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions. Am. J. Surg. Pathol. 25: 579-586.
144. Hruban, R.H., Adsay, N.V., Albores-Saavedra, J., Anver, M.R., Biankin, A.V., Boivin, G.P., Furth, E.E., Furukawa, T., Klein, A., Klimstra, D.S., et al. 2006a. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: Consensus report and recommendations. Cancer Res. 66: 95-106.
145. Hruban, R.H., Bishop Pitman, M., and Klimstra, D.S. 2006b Atlas of tumor pathology: Tumors of the pancreas. Fourth Series (series eds. L.H. Sobin and J. Albores-Saavedra) ARP Press, Washington, DC.
146. Hustinx, S.R., Leoni, L.M., Yeo, C.J., Brown, P.N., Goggins, M., Kern, S.E., Hruban, R.H., and Maitra, A. 2005. Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: Evidence of homozygous deletion in a noninvasive precursor lesion. Mod. Pathol. 18: 959-963.
147. Iacobuzio-Donahue, C.A., Maitra, A., Shen-Ong, G.L., van Heek, T., Ashfaq, R., Meyer, R., Walter, K., Berg, K., Hollingsworth, M.A., Cameron, J.L., et al. 2002. Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am. J. Pathol. 160: 1239-1249.
148. Iacobuzio-Donahue, C.A., Maitra, A., Olsen, M., Lowe, A.W., van Heek, N.T., Rosty, C., Walter, K., Sato, N., Parker, A., Ashfaq, R., et al. 2003. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am. J. Pathol. 162: 1151-1162.
149. Ingham, P.W. and McMahon, A.P. 2001. Hedgehog signaling in animal development: Paradigms and principles. Genes & Dev. 15: 3059-3087.
150. Ishimura, N., Yamasawa, K., Karim Rumi, M.A., Kadowaki, Y., Ishihara, S., Amano, Y., Nio, Y., Higami, T., and Kinoshita, Y. 2003. BRAF and K-ras gene mutations in human pancreatic cancers. Cancer Lett. 199: 169-173.
151. Ishiwata, T., Kornmann, M., Beger, H.G., and Korc, M. 1998. Enhanced fibroblast growth factor 5 expression in stromal and exocrine elements of the pancreas in chronic pancreatitis. Gut 43: 134-139.
152. Itakura, J., Ishiwata, T., Friess, H., Fujii, H., Matsumoto, Y., Buchler, M.W., and Korc, M. 1997. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin. Cancer Res. 3: 1309-1316.
153. Jackson, E.L., Willis, N., Mercer, K., Bronson, R.T., Crowley, D., Montoya, R., Jacks, T., and Tuveson, D.A. 2001. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes & Dev. 15: 3243-3248.
154. Jacobs, J.J. and de Lange, T. 2004. Significant role for p16 in p53-independent telomere-directed senescence. Curr. Biol. 14: 2302-2308.
155. Jaffee, E.M., Hruban, R.H., Canto, M., and Kern, S.E. 2002. Focus on pancreas cancer. Cancer Cell 2: 25-28.
156. Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., Downward, J., Beug, H., and Grunert, S. 2002. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. J. Cell Biol. 156: 299-313.
157. Jaster, R. 2004. Molecular regulation of pancreatic stellate cell function. Mol. Cancer 3: 26.
158. Jenne, D.E., Reimann, H., Nezu, J., Friedel, W., Loff, S., Jeschke, R., Muller, O., Back, W., and Zimmer, M. 1998. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat. Genet. 18: 38-43.
159. Jensen, J., Pedersen, E.E., Galante, P., Hald, J., Heller, R.S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P., and Madsen, O.D. 2000. Control of endodermal endocrine development by Hes-1. Nat. Genet. 24: 36-44.
160. Jhappan, C., Stahle, C., Harkins, R.N., Fausto, N., Smith, G.H., and Merlino, G.T. 1990. TGF α overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61: 1137-1146.
161. Jimenez, R.E., Z'Graggen, K., Hartwig, W., Graeme-Cook, F., Warshaw, A.L., and Fernandez-del Castillo, C. 1999. Immunohistochemical characterization of pancreatic tumors induced by dimethylbenzanthracene in rats. Am. J. Pathol. 154: 1223-1229.
162. Kadesch, T. 2004. Notch signaling: The demise of elegant simplicity. Curr. Opin. Genet. Dev. 14: 506-512.
163. Karin, M. and Ben-Neriah, Y. 2000. Phosphorylation meets ubiquitination: The control of NF-κB activity. Annu. Rev. Immunol. 18: 621-663.
164. Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R.J., and Wright, C.V. 2002. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32: 128-134.
165. Kiaris, H., Politi, K., Grimm, L.M., Szabolcs, M., Fisher, P., Efstratiadis, A., and Artavanis-Tsakonas, S. 2004. Modulation of Notch signaling elicits signature tumors and inhibits hras1-induced oncogenesis in the mouse mammary epithelium. Am. J. Pathol. 165: 695-705.
166. Kim, S.K. and Hebrok, M. 2001. Intercellular signals regulating pancreas development and function. Genes & Dev. 15: 111-127.
167. Kim, C.F., Jackson, E.L., Woolfenden, A.E., Lawrence, S., Babar, I., Vogel, S., Crowley, D., Bronson, R.T., and Jacks, T. 2005. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121: 823-835.
168. Kim, H.J., Schleiffarth, J.R., Jessurun, J., Sumanas, S., Petryk, A., Lin, S., and Ekker, S.C. 2005. Wnt5 signaling in vertebrate pancreas development. BMC Biol. 3: 23.
169. Kinzler, K.W. and Vogelstein, B. 1996. Lessons from hereditary colorectal cancer. Cell 87: 159-170.
170. Kleeff, J., Ishiwata, T., Kumbasar, A., Friess, H., Buchler, M.W., Lander, A.D., and Korc, M. 1998. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J. Clin. Invest. 102: 1662-1673.
171. Kleeff, J., Kothari, N.H., Friess, H., Fan, H., and Korc, M. 2004. Adenovirus-mediated transfer of a truncated fibroblast growth factor (FGF) type I receptor blocks FGF-2 signaling in multiple pancreatic cancer cell lines. Pancreas 28: 25-30.
172. Klimstra, D.S. 1998. Cell lineage in pancreatic neoplasms. In Pancreatic cancer: Advances in molecular pathology, diagnosis & clinical management (eds. F.S. Sarkar and M.C. Duggan), pp. 21-48. Eaton Publishing, Natick, MA.
173. Klimstra, D.S. and Longnecker, D.S. 1994. K-ras mutations in pancreatic ductal proliferative lesions. Am. J. Pathol. 145: 1547-1550.
174. Kobrin, M.S., Yamanaka, Y., Friess, H., Lopez, M.E., and Korc, M. 1993. Aberrant expression of type I fibroblast growth factor receptor in human pancreatic adenocarcinomas. Cancer Res. 53: 4741-4744.
175. Koizumi, M., Doi, R., Toyoda, E., Masui, T., Tulachan, S.S., Kawaguchi, Y., Fujimoto, K., Gittes, G.K., and Imamura, M. 2003. Increased PDX-1 expression is associated with outcome in patients with pancreatic cancer. Surgery 134: 260-266.
176. Kops, G.J., Weaver, B.A., and Cleveland, D.W. 2005. On the road to cancer: Aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer 5: 773-785.
177. Korc, M., Chandrasekar, B., Yamanaka, Y., Friess, H., Buchier, M., and Beger, H.G. 1992. 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 α. J. Clin. Invest. 90: 1352-1360.
178. Kornmann, M., Ishiwata, T., Beger, H.G., and Korc, M. 1997. Fibroblast growth factor-5 stimulates mitogenic signaling and is overexpressed in human pancreatic cancer: Evidence for autocrine and paracrine actions. Oncogene 15: 1417-1424.
179. Kornmann, M., Ishiwata, T., Matsuda, K., Lopez, M.E., Fukahi, K., Asano, G., Beger, H.G., and Korc, M. 2002. IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells. Gastroenterology 123: 301-313.
180. Krimpenfort, P., Quon, K.C., Mooi, W.J., Loonstra, A., and Berns, A. 2001. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413: 83-86.
181. Krishnamurthy, J., Torrice, C., Ramsey, M.R., Kovalev, G.I., Al-Regaiey, K., Su, L., and Sharpless, N.E. 2004. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114: 1299-1307.
182. Kritzik, M.R., Jones, E., Chen, Z., Krakowski, M., Krahl, T., Good, A., Wright, C., Fox, H., and Sarvetnick, N. 1999. PDX-1 and Msx-2 expression in the regenerating and developing pancreas. J. Endocrinol. 163: 523-530.
183. Kuniyasu, H., Abbruzzese, J.L., Cleary, K.R., and Fidler, I.J. 2001. Induction of ductal and stromal hyperplasia by basic fibroblast growth factor produced by human pancreatic carcinoma. Int. J. Oncol. 19: 681-685.
184. Kurahara, H., Takao, S., Maemura, K., Shinchi, H., Natsugoe, S., and Aikou, T. 2004. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: Its relationship to lymph node metastasis. Clin. Cancer Res. 10: 8413-8420.
185. Laghi, L., Orbetegli, O., Bianchi, P., Zerbi, A., Di Carlo, V., Boland, C.R., and Malesci, A. 2002. Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers. Oncogene 21: 4301-4306.
186. Lai, E.C. 2004. Notch signaling: Control of cell communication and cell fate. Development 131: 965-973.
187. Lal, G., Liu, L., Hogg, D., Lassam, N.J., Redston, M.S., and Gallinger, S. 2000. Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosomes Cancer 27: 358-361.
188. Lapidot, T., Sirard, C., Vormoor, J., Murdoch, B., Hoang, T., Caceres-Cortes, J., Minden, M., Paterson, B., Caligiuri, M.A., and Dick, J.E. 1994. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645-648.
189. Lebowitz, P.F., Davide, J.P., and Prendergast, G.C. 1995. Evidence that farnesyltransferase inhibitors suppress Ras transformation by interfering with Rho activity. Mol. Cell. Biol. 15: 6613-6622.
190. Lemoine, N.R., Jain, S., Hughes, C.M., Staddon, S.L., Maillet, B., Hall, P.A., and Kloppel, G. 1992. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 102: 230-236.
191. Lerner, E.C., Zhang, T.T., Knowles, D.B., Qian, Y., Hamilton, A.D., and Sebti, S.M. 1997. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15: 1283-1288.
192. Levy, L. and Hill, C.S. 2005. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol. Cell. Biol. 25: 8108-8125.
193. Lewis, B.C., Klimstra, D.S., and Varmus, H.E. 2003. The c-myc and PyMT oncogenes induce different tumor types in a somatic mouse model for pancreatic cancer. Genes & Dev. 17: 3127-3138.
194. Li, D., Xie, K., Wolff, R., and Abbruzzese, J.L. 2004. Pancreatic cancer. Lancet 363: 1049-1057.
195. Li, J., Kleeff, J., Giese, N., Buchler, M.W., Korc, M., and Friess, H. 2004. Gefitinib ('Iressa,' ZD1839), a selective epidermal growth factor receptor tyrosine kinase inhibitor, inhibits pancreatic cancer cell growth, invasion, and colony formation. Int. J. Oncol. 25: 203-210.
196. Lim, K.H. and Counter, C.M. 2005. Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 8: 381-392.
197. Lim, K.H., Baines, A.T., Fiordalisi, J.J., Shipitsin, M., Feig, L.A., Cox, A.D., Der, C.J., and Counter, C.M. 2005. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7: 533-545.
198. Liptay, S., Weber, C.K., Ludwig, L., Wagner, M., Adler, G., and Schmid, R.M. 2003. Mitogenic and antiapoptotic role of constitutive NF-κB/Rel activity in pancreatic cancer. Int. J. Cancer 105: 735-746.
199. Liu, L., Dilworth, D., Gao, L., Monzon, J., Summers, A., Lassam, N., and Hogg, D. 1999. Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma. Nat. Genet. 21: 128-132.
200. Lizcano, J.M., Goransson, O., Toth, R., Deak, M., Morrice, N.A., Boudeau, J., Hawley, S.A., Udd, L., Makela, T.P., Hardie, D.G., et al. 2004. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23: 833-843.
201. Lohr, M., Maisonneuve, P., and Lowenfels, A.B. 2000. K-Ras mutations and benign pancreatic disease. Int. J. Pancreatol. 27: 93-103.
202. Lohr, M., Schmidt, C., Ringel, J., Kluth, M., Muller, P., Nizze, H., and Jesnowski, R. 2001. Transforming growth factor-β1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61: 550-555.
203. Lowe, S.W. and Sherr, C.J. 2003. Tumor suppression by Ink4a-Arf: Progress and puzzles. Curr. Opin. Genet. Dev. 13: 77-83.
204. Lowenfels, A.B., Maisonneuve, P., DiMagno, E.P., Elitsur, Y., Gates Jr., L.K., Perrault, J., and Whitcomb, D.C. 1997. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. [see comments]. J. Natl. Cancer Inst. 89: 442-446
205. Luttges, J., Schlehe, B., Menke, M.A., Vogel, I., Henne-Bruns, D., and Kloppel, G. 1999. The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 85: 1703-1710.
206. Luttges, J., Galehdari, H., Brocker, V., Schwarte-Waldhoff, I., Henne-Bruns, D., Kloppel, G., Schmiegel, W., and Hahn, S.A. 2001. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am. J. Pathol. 158: 1677-1683.
207. Lynch, H.T., Smyrk, T., Kern, S.E., Hruban, R.H., Lightdale, C.J., Lemon, S.J., Lynch, J.F., Fusaro, L.R., Fusaro, R.M., and Ghadirian, P. 1996. Familial pancreatic cancer: A review. Semin. Oncol. 23: 251-275.
208. Lynch, H.T., Brand, R.E., Hogg, D., Deters, C.A., Fusaro, R.M., Lynch, J.F., Liu, L., Knezetic, J., Lassam, N.J., Goggins, M., et al. 2002. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: The familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 94: 84-96.
209. Mahlamaki, E.H., Hoglund, M., Gorunova, L., Karhu, R., Dawiskiba, S., Andren-Sandberg, A., Kallioniemi, O.P., and Johansson, B. 1997. Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q, and losses of 18q, 9p, and 15q in pancreatic cancer. Genes Chromosomes Cancer 20: 383-391.
210. Mahlamaki, E.H., Barlund, M., Tanner, M., Gorunova, L., Hoglund, M., Karhu, R., and Kallioniemi, A. 2002. Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. Genes Chromosomes Cancer 35: 353-358.
211. Maitland, N.J. and Collins, A. 2005. A tumour stem cell hypothesis for the origins of prostate cancer. BJU Int. 96: 1219-1223.
212. Maitra, A., Adsay, N.V., Argani, P., Iacobuzio-Donahue, C., De Marzo, A., Cameron, J.L., Yeo, C.J., and Hruban, R.H. 2003. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod. Pathol. 16: 902-912.
213. Maitra, A., Fukushima, N., Takaori, K., and Hruban, R.H. 2005.Precursors to invasive pancreatic cancer. Adv. Anat. Pathol. 12: 81-91.
214. Malats, N., Casals, T., Porta, M., Guarner, L., Estivill, X., and Real, F.X. 2001. Cystic fibrosis transmembrane regulator (CFTR) DeltaF508 mutation and 5T allele in patients with chronic pancreatitis and exocrine pancreatic cancer. PANKRAS II Study Group. Gut 48: 70-74.
215. Maloney, E.K., McLaughlin, J.L., Dagdigian, N.E., Garrett, L.M., Connors, K.M., Zhou, X.M., Blattler, W.A., Chittenden, T., and Singh, R. 2003. An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res. 63: 5073-5083.
216. Malumbres, M. and Barbacid, M. 2003. RAS oncogenes: The first 30 years. Nat. Rev. Cancer 3: 459-465.
217. Maser, R.S. and DePinho, R.A. 2002. Connecting chromosomes, crisis, and cancer. Science 297: 565-569.
218. Massague, J., Blain, S.W., and Lo, R.S. 2000. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103: 295-309.
219. Matsubayashi, H., Fukushima, N., Sato, N., Brune, K., Canto, M., Yeo, C.J., Hruban, R.H., Kern, S.E., and Goggins, M. 2003. Polymorphisms of SPINK1 N34S and CFTR in patients with sporadic and familial pancreatic cancer. Cancer Biol. Ther. 2: 652-655.
220. Mayo, M.W., Wang, C.Y., Cogswell, P.C., Rogers-Graham, K.S., Lowe, S.W., Der, C.J., and Baldwin Jr., A.S. 1997. Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278: 1812-1815.
221. McCormick, F. 1998. Going for the GAP. Curr. Biol. 8: R673-R674.
222. McWilliams, R., Highsmith, W.E., Rabe, K.G., de Andrade, M., Tordsen, L.A., Holtegaard, L.M., and Petersen, G.M. 2005. Cystic fibrosis transmembrane regulator gene carrier status is a risk factor for young onset pancreatic adenocarcinoma. Gut 54: 1661-1662.
223. Means, A.L., Meszoely, I.M., Suzuki, K., Miyamoto, Y., Rustgi, A.K., Coffey Jr., R.J., Wright, C.V., Stoffers, D.A., and Leach, S.D. 2005. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132: 3767-3776.
224. Michaud, D.S., Giovannucci, E., Willett, W.C., Colditz, G.A., Stampfer, M.J., and Fuchs, C.S. 2001. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 286: 921-929.
225. Min, Y., Adachi, Y., Yamamoto, H., Ito, H., Itoh, F., Lee, C.T., Nadaf, S., Carbone, D.P., and Imai, K. 2003. Genetic blockade of the insulin-like growth factor-I receptor: A promising strategy for human pancreatic cancer. Cancer Res. 63: 6432-6441.
226. Missiaglia, E., Blaveri, E., Terris, B., Wang, Y.H., Costello, E., Neoptolemos, J.P., Crnogorac-Jurcevic, T., and Lemoine, N.R. 2004. Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasis. Int. J. Cancer 112: 100-112.
227. Mitin, N., Rossman, K.L., and Der, C.J. 2005. Signaling interplay in Ras superfamily function. Curr. Biol. 15: R563-R574.
228. Miyamoto, Y., Maitra, A., Ghosh, B., Zechner, U., Argani, P., Iacobuzio-Donahue, C.A., Sriuranpong, V., Iso, T., Meszoely, I.M., Wolfe, M.S., et al. 2003. Notch mediates TGF α-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3: 565-576.
229. Moshous, D., Callebaut, I., de Chasseval, R., Corneo, B., Cavazzana-Calvo, M., Le Deist, F., Tezcan, I., Sanal, O., Bertrand, Y., Philippe, N., et al. 2001. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105: 177-186.
230. Moskaluk, C.A., Hruban, R.H., and Kern, S.E. 1997. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 57: 2140-2143.
231. Muerkoster, S., Arlt, A., Sipos, B., Witt, M., Grossmann, M., Kloppel, G., Kalthoff, H., Folsch, U.R., and Schafer, H. 2005. Increased expression of the E3-ubiquitin ligase receptor subunit βTRCP1 relates to constitutive nuclear factor-κB activation and chemoresistance in pancreatic carcinoma cells. Cancer Res. 65: 1316-1324.
232. Murphy, K.M., Brune, K.A., Griffin, C., Sollenberger, J.E., Petersen, G.M., Bansal, R., Hruban, R.H., and Kern, S.E. 2002. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%. Cancer Res. 62: 3789-3793.
233. Murtaugh, L.C. and Melton, D.A. 2003. Genes, signals, and lineages in pancreas development. Annu. Rev. Cell Dev. Biol. 19: 71-89.
234. Murtaugh, L.C., Stanger, B.Z., Kwan, K.M., and Melton, D.A. 2003. Notch signaling controls multiple steps of pancreatic differentiation. Proc. Natl. Acad. Sci. 100: 14920-14925.
235. Murtaugh, L.C., Law, A.C., Dor, Y., and Melton, D.A. 2005. β-Catenin is essential for pancreatic acinar but not islet development. Development 132: 4663-4674.
236. Nair, P.N., De Armond, D.T., Adamo, M.L., Strodel, W.E., and Freeman, J.W. 2001. Aberrant expression and activation of insulin-like growth factor-1 receptor (IGF-1R) are mediated by an induction of IGF-1R promoter activity and stabilization of IGF-1R mRNA and contributes to growth factor independence and increased survival of the pancreatic cancer cell line MIA PaCa-2. Oncogene 20: 8203-8214.
237. Nakamura, T., Furukawa, Y., Nakagawa, H., Tsunoda, T., Ohigashi, H., Murata, K., Ishikawa, O., Ohgaki, K., Kashimura, N., Miyamoto, M., et al. 2004. Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 23: 2385-2400.
238. Neglia, J.P., FitzSimmons, S.C., Maisonneuve, P., Schoni, M.H., Schoni-Affolter, F., Corey, M., and Lowenfels, A.B. 1995. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N. Engl. J. Med. 332: 494-499.
239. Ng, S.S.W., Tsao, M.S., Chow, S., and Hedley, D.W. 2000. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res. 60: 5451-5455.
240. Nielsen, G.P., Stemmer-Rachamimov, A.O., Shaw, J., Roy, J.E., Koh, J., and Louis, D.N. 1999. Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab. Invest. 79: 1137-1143.
241. Norgaard, G.A., Jensen, J.N., and Jensen, J. 2003. FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development. Dev. Biol. 264: 323-338.
242. Nowak, N.J., Gaile, D., Conroy, J.M., McQuaid, D., Cowell, J., Carter, R., Goggins, M.G., Hruban, R.H., and Maitra, A. 2005. Genome-wide aberrations in pancreatic adenocarcinoma. Cancer Genet. Cytogenet. 161: 36-50.
243. Offield, M.F., Jetton, T.L., Labosky, P.A., Ray, M., Stein, R.W., Magnuson, M.A., Hogan, B.L., and Wright, C.V. 1996. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122: 983-995.
244. Oft, M., Akhurst, R.J., and Balmain, A. 2002. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat. Cell Biol. 4: 487-494.
245. Ogawa, T., Takayama, K., Takakura, N., Kitano, S., and Ueno, H. 2002. Anti-tumor angiogenesis therapy using soluble receptors: Enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor. Cancer Gene Ther. 9: 633-640.
246. O'Hagan, R.C., Chang, S., Maser, R.S., Mohan, R., Artandi, S.E., Chin, L., and DePinho, R.A. 2002. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2: 149-155.
247. Ohlsson, H., Karlsson, K., and Edlund, T. 1993. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 12: 4251-4259.
248. Ohta, T., Yamamoto, M., Numata, M., Iseki, S., Tsukioka, Y., Miyashita, T., Kayahara, M., Nagakawa, T., Miyazaki, I., Nishikawa, K., et al. 1995. Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas. Br. J. Cancer 72: 824-831.
249. Okami, K., Wu, L., Riggins, G., Cairns, P., Goggins, M., Evron, E., Halachmi, N., Ahrendt, S.A., Reed, A.L., Hilgers, W., et al. 1998. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res. 58: 509-511.
250. Omer, C.A. and Kohl, N.E. 1997. CA1A2X-competitive inhibitors of farnesyltransferase as anti-cancer agents. Trends Pharmacol. Sci. 18: 437-444.
251. Orlowski, R.Z. and Baldwin Jr., A.S. 2002. NF-κB as a therapeutic target in cancer. Trends Mol. Med. 8: 385-389.
252. Ornitz, D.M., Hammer, R.E., Messing, A., Palmiter, R.D., and Brinster, R.L. 1987. Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice. Science 238: 188-193.
253. Orsulic, S. 2002. An RCAS-TVA-based approach to designer mouse models. Mamm. Genome 13: 543-547.
254. Ory, S. and Morrison, D.K. 2004. Signal transduction: Implications for Ras-dependent ERK signaling. Curr. Biol. 14: R277-R278.
255. Ossipova, O., Bardeesy, N., DePinho, R.A., and Green, J.B. 2003. LKB1 (XEEK1) regulates Wnt signalling in vertebrate development. Nat. Cell Biol. 5: 889-894.
256. Ouban, A., Muraca, P., Yeatman, T., and Coppola, D. 2003. Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas. Hum. Pathol. 34: 803-808.
257. Paciucci, R., Vila, M.R., Adell, T., Diaz, V.M., Tora, M., Nakamura, T., and Real, F.X. 1998. Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing Met. Am. J. Pathol. 153: 201-212.
258. Paliwal, S., Pande, S., Kovi, R.C., Sharpless, N.E., Bardeesy, N., and Grossman, S.R. 2006. Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosis. Mol. Cell. Biol. 26: 2360-2372.
259. Pao, W., Klimstra, D.S., Fisher, G.H., and Varmus, H.E. 2003. Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance. Proc. Natl. Acad. Sci. 100: 8764-8769.
260. Pardal, R., Clarke, M.F., and Morrison, S.J. 2003. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer 3: 895-902.
261. Parsa, I., Longnecker, D.S., Scarpelli, D.G., Pour, P., Reddy, J.K., and Lefkowitz, M. 1985. Ductal metaplasia of human exocrine pancreas and its association with carcinoma. Cancer Res. 45: 1285-1290.
262. Pasca di Magliano, M., and Hebrok, M. 2003. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 3: 903-911.
263. Passegue, E., Wagner, E.F., and Weissman, I.L. 2004. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119: 431-443.
264. Peng, B., Fleming, J.B., Breslin, T., Grau, A.M., Fojioka, S., Abbruzzese, J.L., Evans, D.B., Ayers, D., Wathen, K., Wu, T., et al. 2002. Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells. Clin. Cancer Res. 8: 3628-3638.
265. Perugini, R.A., McDade, T.P., Vittimberga Jr., F.J., and Callery, M.P. 2000. Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent. J. Surg. Res. 90: 39-44.
266. Petersen, G.M. and Hruban, R.H. 2003. Familial pancreatic cancer: Where are we in 2003? J. Natl. Cancer Inst. 95: 180-181.
267. Pomerantz, J., Schreiber-Agus, N., Liegeois, N.J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.W., et al. 1998. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92: 713-723.
268. Pour, P.M. 1997. The role of Langerhans islets in pancreatic ductal adenocarcinoma. Front. Biosci. 2: D271-D282.
269. Prasad, N.B., Biankin, A.V., Fukushima, N., Maitra, A., Dhara, S., Elkahloun, A.G., Hruban, R.H., Goggins, M., and Leach, S.D. 2005. Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res. 65: 1619-1626.
270. Prowse, K.R. and Greider, C.W. 1995. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl. Acad. Sci. 92: 4818-4822.
271. Qi, Y., Gregory, M.A., Li, Z., Brousal, J.P., West, K., and Hann, S.R. 2004. p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature 431: 712-717.
272. Quaife, C.J., Pinkert, C.A., Ornitz, D.M., Palmiter, R.D., and Brinster, R.L. 1987. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell 48: 1023-1034.
273. Radtke, F. and Raj, K. 2003. The role of Notch in tumorigenesis: Oncogene or tumour suppressor? Nat. Rev. Cancer 3: 756-767.
274. Rajagopalan, H. and Lengauer, C. 2004. Aneuploidy and cancer. Nature 432: 338-341.
275. Ramirez, R.D., Morales, C.P., Herbert, B.S., Rohde, J.M., Passons, C., Shay, J.W., and Wright, W.E. 2001. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes & Dev. 15: 398-403.
276. Rane, S.G., Lee, J.H., and Lin, H.M. 2006. Transforming growth factor-β pathway: Role in pancreas development and pancreatic disease. Cytokine Growth Factor Rev. 17: 107-119.
277. Rangarajan, A., Hong, S.J., Gifford, A., and Weinberg, R.A. 2004. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6: 171-183.
278. Rocha, S., Campbell, K.J., and Perkins, N.D. 2003. p53- and Mdm2-independent repression of NF-κ B transactivation by the ARF tumor suppressor. Mol. Cell 12: 15-25.
279. Rodriguez-Viciana, P., Warne, P.H., Vanhaesebroeck, B., Waterfield, M.D., and Downward, J. 1996. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J. 15: 2442-2451.
280. Rosty, C., Christa, L., Kuzdzal, S., Baldwin, W.M., Zahurak, M.L., Carnot, F., Chan, D.W., Canto, M., Lillemoe, K.D., Cameron, J.L., et al. 2002. Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology. Cancer Res. 62: 1868-1875.
281. Rowland-Goldsmith, M.A., Maruyama, H., Kusama, T., Ralli, S., and Korc, M. 2001. Soluble type II transforming growth factor-β (TGF-β) receptor inhibits TGF-β signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin. Cancer Res. 7: 2931-2940.
282. Rowland-Goldsmith, M.A., Maruyama, H., Matsuda, K., Idezawa, T., Ralli, M., Ralli, S., and Korc, M. 2002. Soluble type II transforming growth factor-β receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis. Mol. Cancer Ther. 1: 161-167.
283. Rozenblum, E., Schutte, M., Goggins, M., Hahn, S.A., Panzer, S., Zahurak, M., Goodman, S.N., Sohn, T.A., Hruban, R.H., Yeo, C.J., et al. 1997. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 57: 1731-1734.
284. Ruas, M. and Peters, G. 1998. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim. Biophys. Acta 1378: F115-F177.
285. Ruggeri, B.A., Huang, L., Wood, M., Cheng, J.Q., and Testa, J.R. 1998. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 21: 81-86.
286. Sahin, F., Maitra, A., Argani, P., Sato, N., Maehara, N., Montgomery, E., Goggins, M., Hruban, R.H., and Su, G.H. 2003. Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms. Mod. Pathol. 16: 686-691.
287. Saimura, M., Nagai, E., Mizumoto, K., Maehara, N., Minamishima, Y.A., Katano, M., Matsumoto, K., Nakamura, T., and Tanaka, M. 2002. Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4. Clin. Cancer Res. 8: 3243-3249.
288. Samuels, Y. and Velculescu, V.E. 2004. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3: 1221-1224.
289. Sandgren, E.P., Luetteke, N.C., Palmiter, R.D., Brinster, R.L., and Lee, D.C. 1990. Overexpression of TGF α in transgenic mice: Induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61: 1121-1135.
290. Sandgren, E.P., Quaife, C.J., Paulovich, A.G., Palmiter, R.D., and Brinster, R.L. 1991. Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc. Natl. Acad. Sci. 88: 93-97.
291. Sandgren, E.P., Luetteke, N.C., Qiu, T.H., Palmiter, R.D., Brinster, R.L., and Lee, D.C. 1993. Transforming growth factor α dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol. Cell. Biol. 13: 320-330.
292. Sato, N., Mizumoto, K., Nakamura, M., Nakamura, K., Kusumoto, M., Niiyama, H., Ogawa, T., and Tanaka, M. 1999. Centrosome abnormalities in pancreatic ductal carcinoma. Clin. Cancer Res. 5: 963-970.
293. Sato, N., Mizumoto, K., Nakamura, M., Maehara, N., Minamishima, Y.A., Nishio, S., Nagai, E., and Tanaka, M. 2001a. Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells. Cancer Genet. Cytogenet. 126: 13-19.
294. Sato, N., Rosty, C., Jansen, M., Fukushima, N., Ueki, T., Yeo, C.J., Cameron, J.L., Iacobuzio-Donahue, C.A., Hruban, R.H., and Goggins, M. 2001b. STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am. J. Pathol. 159: 2017-2022.
295. Sato, N., Fukushima, N., Maitra, A., Iacobuzio-Donahue, C.A., van Heek, N.T., Cameron, J.L., Yeo, C.J., Hruban, R.H., and Goggins, M. 2004a. Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am. J. Pathol. 164: 903-914.
296. Sato, N., Fukushima, N., Matsubayashi, H., and Goggins, M. 2004b. Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling. Oncogene 23: 1531-1538.
297. Schenk, M., Schwartz, A.G., O'Neal, E., Kinnard, M., Greenson, J.K., Fryzek, J.P., Ying, G.S., and Garabrant, D.H. 2001. Familial risk of pancreatic cancer. J. Natl. Cancer Inst. 93: 640-644.
298. Schleger, C., Arens, N., Zentgraf, H., Bleyl, U., and Verbeke, C. 2000. Identification of frequent chromosomal aberrations in ductal adenocarcinoma of the pancreas by comparative genomic hybridization (CGH). J. Pathol. 191: 27-32.
299. Schlieman, M.G., Fahy, B.N., Ramsamooj, R., Beckett, L., and Bold, R.J. 2003. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br. J. Cancer 89: 2110-2115.
300. Schreiner, B., Baur, D.M., Fingerle, A.A., Zechner, U., Greten, F.R., Adler, G., Sipos, B., Kloppel, G., Hameister, H., and Schmid, R.M. 2003. Pattern of secondary genomic changes in pancreatic tumors of Tgfα/Trp53+/- transgenic mice. Genes Chromosomes Cancer 38: 240-248.
301. Schwarte-Waldhoff, I., Volpert, O.V., Bouck, N.P., Sipos, B., Hahn, S.A., Klein-Scory, S., Luttges, J., Kloppel, G., Graeven, U., Eilert-Micus, C., et al. 2000. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc. Natl. Acad. Sci. 97: 9624-9629.
302. Sclabas, G.M., Fujioka, S., Schmidt, C., Evans, D.B., and Chiao, P.J. 2003. NF-κB in pancreatic cancer. Int. J. Gastrointest. Cancer 33: 15-26.
303. Scoggins, C.R., Meszoely, I.M., Wada, M., Means, A.L., Yang, L., and Leach, S.D. 2000. p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 279: G827-G836.
304. Seo, Y., Baba, H., Fukuda, T., Takashima, M., and Sugimachi, K. 2000. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88: 2239-2245.
305. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W. 1997. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593-602.
306. Shah, S.A., Potter, M.W., Hedeshian, M.H., Kim, R.D., Chari, R.S., and Callery, M.P. 2001. PI-3′ kinase and NF-κB cross-signaling in human pancreatic cancer cells. J. Gastrointest. Surg. 5: 603-612; discussion 612-613.
307. Sharer, N., Schwarz, M., Malone, G., Howarth, A., Painter, J., Super, M., and Braganza, J. 1998. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N. Engl. J. Med. 339: 645-652.
308. Sharma, A., Zangen, D.H., Reitz, P., Taneja, M., Lissauer, M.E., Miller, C.P., Weir, G.C., Habener, J.F., and Bonner-Weir, S. 1999. The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 48: 507-513.
309. Sharpless, N.E. and DePinho, R.A. 1999. The INK4A/ARF locus and its two gene products. Curr. Opin. Genet. Dev. 9: 22-30.
310. _. 2002. p53: Good cop/bad cop. Cell 110: 9-12.
311. _. 2005. Cancer: Crime and punishment. Nature 436: 636-637.
312. Sharpless, N.E., Bardeesy, N., Lee, K.H., Carrasco, D., Castrillon, D.H., Aguirre, A.J., Wu, E.A., Horner, J.W., and DePinho, R.A. 2001a. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413: 86-91.
313. Sharpless, N.E., Ferguson, D.O., O'Hagan, R.C., Castrillon, D.H., Lee, C., Farazi, P.A., Alson, S., Fleming, J., Morton, C.C., Frank, K., et al. 2001b.
314. Shaw, R.J., Bardeesy, N., Manning, B.D., Lopez, L., Kosmatka, M., DePinho, R.A., and Cantley, L.C. 2004a. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6: 91-99.
315. Shaw, R.J., Kosmatka, M., Bardeesy, N., Hurley, R.L., Witters, L.A., DePinho, R.A., and Cantley, L.C. 2004b. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. 101: 3329-3335.
316. Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.H., Bardeesy, N., Depinho, R.A., Montminy, M., and Cantley, L.C. 2005. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642-1646.
317. Sherr, C.J. 2001. The INK4a/ARF network in tumour suppression. Nat. Rev. Mol. Cell Biol. 2: 731-737.
318. Sherr, C.J. and DePinho, R.A. 2000. Cellular senescence: Mitotic clock or culture shock? Cell 102: 407-410.
319. Siegel, P.M. and Massague, J. 2003. Cytostatic and apoptotic actions of TGF-α in homeostasis and cancer. Nat. Rev. Cancer 3: 807-821.
320. Signoretti, S., Waltregny, D., Dilks, J., Isaac, B., Lin, D., Garraway, L., Yang, A., Montironi, R., McKeon, F., and Loda, M. 2000. p63 is a prostate basal cell marker and is required for prostate development. Am. J. Pathol. 157: 1769-1775.
321. Singh, S.K., Clarke, I.D., Hide, T., and Dirks, P.B. 2004a. Cancer stem cells in nervous system tumors. Oncogene 23: 7267-7273.
322. Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Hide, T., Henkelman, R.M., Cusimano, M.D., and Dirks, P.B. 2004b. Identification of human brain tumour initiating cells. Nature 432: 396-401.
323. Sirivatanauksorn, V., Sirivatanauksorn, Y., Gorman, P.A., Davidson, J.M., Sheer, D., Moore, P.S., Scarpa, A., Edwards, P.A., and Lemoine, N.R. 2001. Non-random chromosomal rearrangements in pancreatic cancer cell lines identified by spectral karyotyping. Int. J. Cancer 91: 350-358.
324. Sjolund, J., Manetopoulos, C., Stockhausen, M.T., and Axelson, H. 2005. The Notch pathway in cancer: Differentiation gone awry. Eur. J. Cancer 41: 2620-2629.
325. Solcia, E., Capella, C., and Kloppel, G. 1995. Tumors of the pancreas. Armed Forces Institute for Pathology, Washington, DC.
326. Stanger, B.Z., Stiles, B., Lauwers, G.Y., Bardeesy, N., Mendoza, M., Wang, Y., Greenwood, A., Cheng, K.H., McLaughlin, M., Brown, D., et al. 2005. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 8: 185-195.
327. Stoeltzing, O., Liu, W., Reinmuth, N., Fan, F., Parikh, A.A., Bucana, C.D., Evans, D.B., Semenza, G.L., and Ellis, L.M. 2003. Regulation of hypoxia-inducible factor-1α, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer. Am. J. Pathol. 163: 1001-1011.
328. Stolzenberg-Solomon, R.Z., Graubard, B.I., Chari, S., Limburg, P., Taylor, P.R., Virtamo, J., and Albanes, D. 2005. Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 294: 2872-2878.
329. Storchova, Z. and Pellman, D. 2004. From polyploidy to aneuploidy, genome instability and cancer. Nat. Rev. Mol. Cell Biol. 5: 45-54.
330. Su, G.H., Hruban, R.H., Bansal, R.K., Bova, G.S., Tang, D.J., Shekher, M.C., Westerman, A.M., Entius, M.M., Goggins, M., Yeo, C.J., et al. 1999. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am. J. Pathol. 154: 1835-1840.
331. Sugimoto, M., Kuo, M.L., Roussel, M.F., and Sherr, C.J. 2003. Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Mol. Cell 11: 415-424.
332. Sundaram, M.V. 2005. The love-hate relationship between Ras and Notch. Genes & Dev. 19: 1825-1839.
333. Suwa, H., Ohshio, G., Imamura, T., Watanabe, G., Arii, S., Imamura, M., Narumiya, S., Hiai, H., and Fukumoto, M. 1998. Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br. J. Cancer 77: 147-152.
334. Sweet-Cordero, A., Mukherjee, S., Subramanian, A., You, H., Roix, J.J., Ladd-Acosta, C., Mesirov, J., Golub, T.R., and Jacks, T. 2005. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nat. Genet. 37: 48-55.
335. Taipale, J. and Beachy, P.A. 2001. The Hedgehog and Wnt signalling pathways in cancer. Nature 411: 349-354.
336. Tang, R.F., Itakura, J., Aikawa, T., Matsuda, K., Fujii, H., Korc, M., and Matsumoto, Y. 2001. Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer. Pancreas 22: 285-292.
337. Tang, B., Vu, M., Booker, T., Santner, S.J., Miller, F.R., Anver, M.R., and Wakefield, L.M. 2003. TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J. Clin. Invest. 112: 1116-1124.
338. Taniguchi, T., Tischkowitz, M., Ameziane, N., Hodgson, S.V., Mathew, C.G., Joenje, H., Mok, S.C., and D'Andrea, A.D. 2003. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat. Med. 9: 568-574.
339. Tascilar, M., Skinner, H.G., Rosty, C., Sohn, T., Wilentz, R.E., Offerhaus, G.J., Adsay, V., Abrams, R.A., Cameron, J.L., Kern, S.E., et al. 2001. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 7: 4115-4121.
340. ten Dijke, P. and Hill, C.S. 2004. New insights into TGF-β-Smad signalling. Trends Biochem. Sci. 29: 265-273.
341. Thayer, S.P., di Magliano, M.P., Heiser, P.W., Nielsen, C.M., Roberts, D.J., Lauwers, G.Y., Qi, Y.P., Gysin, S., Fernandez-del Castillo, C., Yajnik, V., et al. 2003. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425: 851-856.
342. Thomas, A.M., Santarsiero, L.M., Lutz, E.R., Armstrong, T.D., Chen, Y.C., Huang, L.Q., Laheru, D.A., Goggins, M., Hruban, R.H., and Jaffee, E.M. 2004. Mesothelin-specific CD8+ T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J. Exp. Med. 200: 297-306.
343. Thompson, D. and Easton, D.F. 2002. Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 94: 1358-1365.
344. Tokunaga, T., Abe, Y., Tsuchida, T., Hatanaka, H., Oshika, Y., Tomisawa, M., Yoshimura, M., Ohnishi, Y., Kijima, H., Yamazaki, H., et al. 2002. Ribozyme mediated cleavage of cell-associated isoform of vascular endothelial growth factor inhibits liver metastasis of a pancreatic cancer cell line. Int. J. Oncol. 21: 1027-1032.
345. Tomioka, D., Maehara, N., Kuba, K., Mizumoto, K., Tanaka, M., Matsumoto, K., and Nakamura, T. 2001. Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 61: 7518-7524.
346. Tonon, G., Wong, K.K., Maulik, G., Brennan, C., Feng, B., Zhang, Y., Khatry, D.B., Protopopov, A., You, M.J., Aguirre, A.J., et al. 2005. High-resolution genomic profiles of human lung cancer. Proc. Natl. Acad. Sci. 102: 9625-9630.
347. Tosh, D. and Slack, J.M. 2002. How cells change their phenotype. Nat. Rev. Mol. Cell Biol. 3: 187-194.
348. Tuveson, D.A., Shaw, A.T., Willis, N.A., Silver, D.P., Jackson, E.L., Chang, S., Mercer, K.L., Grochow, R., Hock, H., Crowley, D., et al. 2004. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5: 375-387.
349. Tuveson, D.A., Zhu, L., Gopinathan, A., Willis, N.A., Kachatrian, L., Grochow, R., Pin, C.L., Mitin, N.Y., Taparowsky, E.J., Gimotty, P.A., et al. 2006. Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma. Cancer Res. 66: 242-247.
350. Van Cutsem, E., van de Velde, H., Karasek, P., Oettle, H., Vervenne, W.L., Szawlowski, A., Schoffski, P., Post, S., Verslype, C., Neumann, H., et al. 2004. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22: 1430-1438.
351. van der Heijden, M.S., Brody, J.R., Gallmeier, E., Cunningham, S.C., Dezentje, D.A., Shen, D., Hruban, R.H., and Kern, S.E. 2004. Functional defects in the Fanconi anemia pathway in pancreatic cancer cells. Am. J. Pathol. 165: 651-657.
352. Van Dyke, T. and Jacks, T. 2002. Cancer modeling in the modern era: Progress and challenges. Cell 108: 135-144.
353. van Heek, N.T., Meeker, A.K., Kern, S.E., Yeo, C.J., Lillemoe, K.D., Cameron, J.L., Offerhaus, G.J., Hicks, J.L., Wilentz, R.E., Goggins, M.G., et al. 2002. Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am. J. Pathol. 161: 1541-1547.
354. Venkitaraman, A.R. 2002. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108: 171-182.
355. Vinik, A.I., Pittenger, G.L., Rafaeloff, R., Rosenberg, L., and Duguid, W. 1997. Determinants of pancreatic iselt cell neogenesis - The cellophane wrap model. In Pancreatic growth and regeneration (ed. N. Sarvetnick), pp. 183-217. Karger Landes Systems, Basel, Switzerland.
356. Vivanco, I. and Sawyers, C.L. 2002. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2: 489-501.
357. von Marschall, Z., Cramer, T., Hocker, M., Burde, R., Plath, T., Schirner, M., Heidenreich, R., Breier, G., Riecken, E.O., Wiedenmann, B., et al. 2000. De novo expression of vascular endothelial growth factor in human pancreatic cancer: Evidence for an autocrine mitogenic loop. Gastroenterology 119: 1358-1372.
358. Wagner, M., Lopez, M.E., Cahn, M., and Korc, M. 1998a. Suppression of fibroblast growth factor receptor signaling inhibits pancreatic cancer growth in vitro and in vivo. Gastroenterology 114: 798-807.
359. Wagner, M., Luhrs, H., Kloppel, G., Adler, G., and Schmid, R.M. 1998b. Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice. Gastroenterology 115: 1254-1262.
360. Wagner, M., Kleeff, J., Friess, H., Buchler, M.W., and Korc, M. 1999. Enhanced expression of the type II transforming growth factor-β receptor is associated with decreased survival in human pancreatic cancer. Pancreas 19: 370-376.
361. Wagner, M., Greten, F.R., Weber, C.K., Koschnick, S., Mattfeldt, T., Deppert, W., Kern, H., Adler, G., and Schmid, R.M. 2001. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes & Dev. 15: 286-293.
362. Wang, R.N., Rehfeld, J.F., Nielsen, F.C., and Kloppel, G. 1997. Expression of gastrin and transforming growth factor-α during duct to islet cell differentiation in the pancreas of ductligated adult rats. Diabetologia 40: 887-893.
363. Wang, W., Abbruzzese, J.L., Evans, D.B., Larry, L., Cleary, K.R., and Chiao, P.J. 1999. The nuclear factor-κ B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin. Cancer Res. 5: 119-127.
364. Warshaw, A.L. and Fernandez-del Castillo, C. 1992. Pancreatic carcinoma. N. Engl. J. Med. 326: 455-465.
365. Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S.M., Zlobin, A., Osborne, B.A., Gottipati, S., Aster, J.C., Hahn, W.C., et al. 2002. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat. Med. 8: 979-986.
366. Wennerberg, K., Rossman, K.L., and Der, C.J. 2005. The Ras superfamily at a glance. J. Cell Sci. 118: 843-846.
367. Whelan, A.J., Bartsch, D., and Goodfellow, P.J. 1995. Brief report: A familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene [see comments]. N. Engl. J. Med. 333: 975-977.
368. Whitcomb, D.C., Gorry, M.C., Preston, R.A., Furey, W., Sossenheimer, M.J., Ulrich, C.D., Martin, S.P., Gates Jr., L.K., Amann, S.T., Toskes, P.P., et al. 1996. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene [see comments]. Nat. Genet. 14: 141-145.
369. Wilentz, R.E., Geradts, J., Maynard, R., Offerhaus, G.J., Kang, M., Goggins, M., Yeo, C.J., Kern, S.E., and Hruban, R.H. 1998. Inactivation of the p16(INK4A) tumor-suppressor gene in pancreatic duct lesions: Loss of intranuclear expression. Cancer Res. 58: 4740-4744.
370. Wilentz, R.E., Iacobuzio-Donahue, C.A., Argani, P., McCarthy, D.M., Parsons, J.L., Yeo, C.J., Kern, S.E., and Hruban, R.H. 2000. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 60: 2002-2006.
371. Wittinghofer, A., Scheffzek, K., and Ahmadian, M.R. 1997. The interaction of Ras with GTPase-activating proteins. FEBS Lett. 410: 63-67.
372. Woo, R.A. and Poon, R.Y. 2004. Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation. Genes & Dev. 18: 1317-1330.
373. Xing, H.R., Cordon-Cardo, C., Deng, X., Tong, W., Campodonico, L., Fuks, Z., and Kolesnick, R. 2003. Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer. Nat. Med. 9: 1266-1268.
374. Xiong, H.Q., Abbruzzese, J.L., Lin, E., Wang, L., Zheng, L., and Xie, K. 2004. NF-κB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int. J. Cancer 108: 181-188.
375. Yamanaka, Y., Friess, H., Buchler, M., Beger, H.G., Uchida, E., Onda, M., Kobrin, M.S., and Korc, M. 1993a. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res. 53: 5289-5296.
376. Yamanaka, Y., Friess, H., Kobrin, M.S., Buchler, M., Beger, H.G., and Korc, M. 1993b. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res. 13: 565-569.
377. Yamano, M., Fujii, H., Takagaki, T., Kadowaki, N., Watanabe, H., and Shirai, T. 2000. Genetic progression and divergence in pancreatic carcinoma. Am. J. Pathol. 156: 2123-2133.
378. Yoshida, T. and Hanahan, D. 1994. Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans. Am. J. Pathol. 145: 671-684.
379. Zavadil, J. and Bottinger, E.P. 2005. TGF-β and epithelial- tomesenchymal transitions. Oncogene 24: 5764-5774.
380. Zhang, Y., Xiong, Y., and Yarbrough, W.G. 1998. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92: 725-734.
381. Zhu, J., Woods, D., McMahon, M., and Bishop, J.M. 1998. Senescence of human fibroblasts induced by oncogenic Raf. Genes & Dev. 12: 2997-3007.
382. Zindy, F., Quelle, D.E., Roussel, M.F., and Sherr, C.J. 1997. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15: 203-211.