Molecular biology of pancreatic ductal adenocarcinoma progression: Aberrant activation of developmental pathways

Progress in Molecular Biology and Translational Science

Volumn 97, Issue C, 2010, Pages 41-78

  Rhim, Andrew D ^a,b   Stanger, Ben Z ^a,b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Development; Hedgehog; Kras; Metastasis; Mouse model; Notch; Pancreatic ductal adenocarcinoma; Pancreatic intraepithelial neoplasia; Signaling; TGF

Indexed keywords

EID: 78649272579     PISSN: 18771173     EISSN: None     Source Type: Book Series    
DOI: 10.1016/B978-0-12-385233-5.00002-7     Document Type: Chapter

References (222)

1. SEER N. http://seercancergov/ 2009
2. J.M. Winter, J.L. Cameron, K.A. Campbell, M.A. Arnold, D.C. Chang, J. Coleman, M.B. Hodgin, P.K. Sauter, R.H. Hruban, and T.S. Riall 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience J Gastrointest Surg 10 2006 1199 1210 discussion 12101191
3. D. Hanahan, and R.A. Weinberg The hallmarks of cancer Cell 100 2000 57 70
4. H. Algul, M. Treiber, M. Lesina, and R.M. Schmid Mechanisms of disease: chronic inflammation and cancer in the pancreasa potential role for pancreatic stellate cells? Nat Clin Pract Gastroenterol Hepatol 4 2007 454 462
5. A. Masamune, T. Watanabe, K. Kikuta, and T. Shimosegawa Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis Clin Gastroenterol Hepatol 7 2009 S48 54
6. A.F. Hezel, A.C. Kimmelman, B.Z. Stanger, N. Bardeesy, and R.A. Depinho Genetics and biology of pancreatic ductal adenocarcinoma Genes Dev 20 2006 1218 1249
7. D. Stafford, and V.E. Prince Retinoic acid signaling is required for a critical early step in zebrafish pancreatic development Curr Biol 12 2002 1215 1220
8. N. Tiso, A. Filippi, S. Pauls, M. Bortolussi, and F. Argenton BMP signalling regulates anteroposterior endoderm patterning in zebrafish Mech Dev 118 2002 29 37
9. R.L. Pictet, W.R. Clark, R.H. Williams, and W.J. Rutter An ultrastructural analysis of the developing embryonic pancreas Dev Biol 29 1972 436 467
10. N. Wessells, and J. Cohen Early pancreas organogenesis: morphogenesis, tissue interactions, and mass effects Dev Biol 15 1967 237 270
11. S. Kim, M. Hebrok, and D. Melton Notochord to endoderm signaling is required for pancreas development Development 124 1997 4243 4252
12. B. Hogan Morphogenesis Cell 96 1999 225 233
13. K. Manova, V. De Leon, M. Angeles, S. Kalantry, M. Giarre, L. Attisano, J. Wrana, and R.F. Bachvarova mRNAs for activin receptors II and IIB are expressed in mouse oocytes and in the epiblast of pregastrula and gastrula stage mouse embryos Mech Dev 49 1995 3 11
14. K. Verschueren, N. Dewulf, M.J. Goumans, O. Lonnoy, A. Feijen, S. Grimsby, K. Vandi Spiegle, P. ten Dijke, A. Moren, and P. Vanscheeuwijck Expression of type I and type IB receptors for activin in midgestation mouse embryos suggests distinct functions in organogenesis Mech Dev 52 1995 109 123
15. M. Hebrok, S. Kim, and D. Melton Notochord repression of endodermal Sonic hedgehog permits pancreas development Genes Dev 12 1998 1705 1713
16. A. Apelqvist, U. Ahlgren, and H. Edlund Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas Curr Biol 7 1997 801 804
17. M. Hebrok, S. Kim, B. St-Jacques, A. McMahon, and D. Melton Regulation of pancreas development by hedgehog signaling Development 127 2000 4905 4913
18. J. Jonsson, L. Carlsson, T. Edlund, and H. Edlund Insulin-promoter-factor 1 is required for pancreas development in mice Nature 371 1994 606 609
19. M.F. Offield, T.L. Jetton, P.A. Labosky, M. Ray, R.W. Stein, M.A. Magnuson, B.L. Hogan, and C.V. Wright PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum Development 122 1996 983 995
20. U. Ahlgren, J. Jonsson, and H. Edlund The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice Development 122 1996 1409 1416
21. A. Hart, N. Baeza, A. Apelqvist, and H. Edlund Attenuation of FGF signalling in mouse b-cells leads to diabetes Nature 408 2000 864 868
22. G.A. Norgaard, J.N. Jensen, and J. Jensen FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development Dev Biol 264 2003 323 338
23. E. Lammert, O. Cleaver, and D. Melton Induction of pancreatic differentiation by signals from blood vessels Science 294 2001 564 567
24. E. Lammert, G. Gu, M. McLaughlin, D. Brown, R. Brekken, L.C. Murtaugh, H.P. Gerber, N. Ferrara, and D.A. Melton Role of VEGF-A in vascularization of pancreatic islets Curr Biol 13 2003 1070 1074
25. P. Jacquemin, H. Yoshitomi, Y. Kashima, G.G. Rousseau, F.P. Lemaigre, and K.S. Zaret An endothelial-mesenchymal relay pathway regulates early phases of pancreas development Dev Biol 290 2006 189 199
26. A. Krapp, M. Knofler, S. Frutiger, G.J. Hughes, O. Hagenbuchle, and P.K. Wellauer The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein EMBO J 15 1996 4317 4329
27. H. Yoshitomi, and K.S. Zaret Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a Development 131 2004 807 817
28. F. Kallman, and C. Grobstein Fine structure of differentiating mouse pancreatic exocrine cells in transfilter culture J Cell Biol 20 1964 399 413
29. B.L. Munger A light and electron microscopic study of cellular differentiation in the pancreatic islets of the mouse Am J Anat 103 1958 275 311
30. J. Slack Developmental biology of the pancreas Development 121 1995 1569 1580
31. J.W. Theunissen, and F.J. de Sauvage Paracrine hedgehog signaling in cancer Cancer Res 69 2009 6007 6010
32. S.B. Smith, H. Watada, D.W. Scheel, C. Mrejen, and M.S. German Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter J Biol Chem 275 2000 36910 36919
33. D. Ornitz, and N. Itoh Fibroblast growth factors Genome Biol 2 3005 2001 3001 3012
34. M. Goldfarb Signaling by fibroblast growth factors: the inside story Sci STKE 2001 pe37
35. I. Manfroid, F. Delporte, A. Baudhuin, P. Motte, C.J. Neumann, M.L. Voz, J.A. Martial, and B. Peers Reciprocal endodermmesoderm interactions mediated by fgf24 and fgf10 govern pancreas development Development 134 2007 4011 4021
36. F. Miralles, L. Lamotte, D. Couton, and R.L. Joshi Interplay between FGF10 and Notch signalling is required for the self-renewal of pancreatic progenitors Int J Dev Biol 50 2006 17 26
37. D.S. Dichmann, C.P. Miller, J. Jensen, R. Scott Heller, and P. Serup Expression and misexpression of members of the FGF and TGFbeta families of growth factors in the developing mouse pancreas Dev Dyn 226 2003 663 674
38. S. LeBras, P. Czernichow, and R. Scharfmann A search for tyrosine kinase receptors expressed in the rat embryonic pancreas Diabetologia 41 1998 1474 1481
39. M.A. Pulkkinen, B. Spencer-Dene, C. Dickson, and T. Otonkoski The IIIb isoform of fibroblast growth factor receptor 2 is required for proper growth and branching of pancreatic ductal epithelium but not for differentiation of exocrine or endocrine cells Mech Dev 120 2003 167 175
40. G. Deutsch, J. Jung, M. Zheng, J. Lora, and K. Zaret A bipotential precursor population for pancreas and liver within the embryonic endoderm Development 128 2001 871 881
41. G. Celli, W.J. LaRochelle, S. Mackem, R. Sharp, and G. Merlino Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning EMBO J 17 1998 1642 1655
42. L. Elghazi, C. Cras-Meneur, P. Czernichow, and R. Scharfmann Role for FGFR2IIIb-mediated signals in controlling pancreatic endocrine progenitor cell proliferation Proc Natl Acad Sci USA 99 2002 3884 3889
43. F. Ye, B. Duvillie, and R. Scharfmann Fibroblast growth factors 7 and 10 are expressed in the human embryonic pancreatic mesenchyme and promote the proliferation of embryonic pancreatic epithelial cells Diabetologia 48 2005 277 281
44. A. Bhushan, N. Itoh, S. Kato, J. Thiery, P. Czernichow, S. Bellusci, and R. Scharfmann Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis Development 128 2001 5109 5117
45. A. Hart, S. Papadopoulou, and H. Edlund Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells Dev Dyn 228 2003 185 193
46. S. Arnaud-Dabernat, M. Kritzik, A.G. Kayali, Y.Q. Zhang, G. Liu, C. Ungles, and N. Sarvetnick FGFR3 is a negative regulator of the expansion of pancreatic epithelial cells Diabetes 56 2007 96 106
47. A. Apelqvist, H. Li, L. Sommer, P. Beatus, D.J. Anderson, T. Honjo, M. Hrabe de Angelis, U. Lendahl, and H. Edlund Notch signalling controls pancreatic cell differentiation Nature 400 1999 877 881
48. R.A. Conlon, A.G. Reaume, and J. Rossant Notch1 is required for the coordinate segmentation of somites Development 121 1995 1533 1545
49. M. Hrabe de Angelis, J. McIntyre 2nd, and A. Gossler Maintenance of somite borders in mice requires the Delta homologue DII1 Nature 386 1997 717 721
50. T.M. Beres, T. Masui, G.H. Swift, L. Shi, R.M. Henke, and R.J. MacDonald PTF1 is an organ-specific and Notch-independent basic helix-loop-helix complex containing the mammalian Suppressor of Hairless (RBP-J) or its paralogue, RBP-L Mol Cell Biol 26 2006 117 130
51. S. Georgia, R. Soliz, M. Li, P. Zhang, and A. Bhushan p57 and Hes1 coordinate cell cycle exit with self-renewal of pancreatic progenitors Dev Biol 298 2006 22 31
52. T. Yoshida, A. Tokunaga, K. Nakao, and H. Okano Distinct expression patterns of splicing isoforms of mNumb in the endocrine lineage of developing pancreas Differentiation 71 2003 486 495
53. F. Esni, B. Ghosh, A.V. Biankin, J.W. Lin, M.A. Albert, X. Yu, R.J. MacDonald, C.I. Civin, F.X. Real, and M.A. Pack Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas Development 131 2004 4213 4224
54. J. Hald, J.P. Hjorth, M.S. German, O.D. Madsen, P. Serup, and J. Jensen Activated Notch1 prevents differentiation of pancreatic acinar cells and attenuate endocrine development Dev Biol 260 2003 426 437
55. L.C. Murtaugh, B.Z. Stanger, K.M. Kwan, and D.A. Melton Notch signaling controls multiple steps of pancreatic differentiation Proc Natl Acad Sci USA 100 2003 14920 14925
56. Y. Xu, S. Wang, J. Zhang, A. Zhao, B.Z. Stanger, and G. Gu The fringe molecules induce endocrine differentiation in embryonic endoderm by activating cMyt1/cMyt3 Dev Biol 297 2006 340 349
57. K.A. Johansson, U. Dursun, N. Jordan, G. Gu, F. Beermann, G. Gradwohl, and A. Grapin-Botton Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types Dev Cell 12 2007 457 465
58. M.L. Golson, J. Le Lay, N. Gao, N. Bramswig, K.M. Loomes, R. Oakey, C.L. May, P. White, and K.H. Kaestner Jagged1 is a competitive inhibitor of Notch signaling in the embryonic pancreas Mech Dev 126 2009 687 699
59. Y. Miyamoto, A. Maitra, B. Ghosh, U. Zechner, P. Argani, C.A. Iacobuzio-Donahue, V. Sriuranpong, T. Iso, I.M. Meszoely, and M.S. Wolfe Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis Cancer Cell 3 2003 565 576
60. M. Rovira, S.G. Scott, A.S. Liss, J. Jensen, S.P. Thayer, and S.D. Leach Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas Proc Natl Acad Sci USA 107 2010 75 80
61. B.Z. Stanger, and Y. Dor Dissecting the cellular origins of pancreatic cancer Cell Cycle 5 2006 43 46
62. G.K. Gittes Developmental biology of the pancreas: a comprehensive review Dev Biol 326 2009 4 35
63. S.G. Rane, J.H. Lee, and H.M. Lin Transforming growth factor-beta pathway: role in pancreas development and pancreatic disease Cytokine Growth Factor Rev 17 2006 107 119
64. C.A. Crisera, T.S. Maldonado, A.S. Kadison, M. Li, S.L. Alkasab, M.T. Longaker, and G.K. Gittes Transforming growth factor-beta 1 in the developing mouse pancreas: a potential regulator of exocrine differentiation Differentiation 65 2000 255 259
65. N.L. Thompson, K.C. Flanders, J.M. Smith, L.R. Ellingsworth, A.B. Roberts, and M.B. Sporn Expression of transforming growth factor-beta 1 in specific cells and tissues of adult and neonatal mice J Cell Biol 108 1989 661 669
66. C.A. Crisera, M.I. Rose, P.R. Connelly, M. Li, K.L. Colen, M.T. Longaker, and G.K. Gittes The ontogeny of TGF-beta1, -beta2, -beta3, and TGF-beta receptor-II expression in the pancreas: implications for regulation of growth and differentiation J Pediatr Surg 34 68993 1999 684 693 discussion
67. E.P. Bottinger, J.L. Jakubczak, I.S. Roberts, M. Mumy, P. Hemmati, K. Bagnall, G. Merlino, and L.M. Wakefield Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas EMBO J 16 1997 2621 2633
68. M. Furukawa, R. Nobusawa, H. Shibata, Y. Eto, and I. Kojima Initiation of insulin secretion in glucose-free medium by activin A Mol Cell Endocrinol 113 1995 83 87
69. T.S. Maldonado, A.S. Kadison, C.A. Crisera, J.B. Grau, S.L. Alkasab, M.T. Longaker, and G.K. Gittes Ontogeny of activin B and follistatin in developing embryonic mouse pancreas: implications for lineage selection J Gastrointest Surg 4 2000 269 275
70. F. Miralles, P. Czernichow, and R. Scharfmann Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development Development 125 1998 1017 1024
71. O. Ritvos, T. Tuuri, M. Eramaa, K. Sainio, K. Hilden, L. Saxen, and S.F. Gilbert Activin disrupts epithelial branching morphogenesis in developing glandular organs of the mouse Mech Dev 50 1995 229 245
72. S. Sulzbacher, I.S. Schroeder, T.T. Truong, and A.M. Wobus Activin A-induced differentiation of embryonic stem cells into endoderm and pancreatic progenitors-the influence of differentiation factors and culture conditions Stem Cell Rev 5 2009 159 173
73. J. Ahnfelt-Ronne, P. Ravassard, C. Pardanaud-Galvieux, R. Scharfmann, and P. Serup Mesenchymal Bmp signalling is required for normal pancreas development Diabetes 8 2010 1948 1956
74. J. Goulley, U. Dahl, N. Baeza, Y. Mishina, and H. Edlund BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion Cell Metab 5 2007 207 219
75. E.B. Harmon, A.A. Apelqvist, N.G. Smart, X. Gu, D.H. Osborne, and S.K. Kim GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development Development 131 2004 6163 6174
76. P. Jacquemin, S.M. Durviaux, J. Jensen, C. Godfraind, G. Gradwohl, F. Guillemot, O.D. Madsen, P. Carmeliet, M. Dewerchin, and D. Collen Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3 Mol Cell Biol 20 2000 4445 4454
77. D.S. Dichmann, H. Yassin, and P. Serup Analysis of pancreatic endocrine development in GDF11-deficient mice Dev Dyn 235 2006 3016 3025
78. M.M. McGrane Vitamin A regulation of gene expression: molecular mechanism of a prototype gene J Nutr Biochem 18 2007 497 508
79. M. Martin, J. Gallego-Llamas, V. Ribes, M. Kedinger, K. Niederreither, P. Chambon, P. Dolle, and G. Gradwohl Dorsal pancreas agenesis in retinoic acid-deficient Raldh2 mutant mice Dev Biol 284 2005 399 411
80. D. Stafford, R.J. White, M.D. Kinkel, A. Linville, T.F. Schilling, and V.E. Prince Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells Development 133 2006 949 956
81. A. Molotkov, N. Molotkova, and G. Duester Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development Dev Dyn 232 2005 950 957
82. H. Kobayashi, T.L. Spilde, A.M. Bhatia, R.B. Buckingham, M.J. Hembree, K. Prasadan, B.L. Preuett, M. Imamura, and G.K. Gittes Retinoid signaling controls mouse pancreatic exocrine lineage selection through epithelialmesenchymal interactions Gastroenterology 123 2002 1331 1340
83. M.A. Huotari, P.J. Miettinen, J. Palgi, T. Koivisto, J. Ustinov, D. Harari, Y. Yarden, and T. Otonkoski ErbB signaling regulates lineage determination of developing pancreatic islet cells in embryonic organ culture Endocrinology 143 2002 4437 4446
84. C. Cras-Meneur, L. Elghazi, P. Czernichow, and R. Scharfmann Epidermal growth factor increases undifferentiated pancreatic embryonic cells in vitro: a balance between proliferation and differentiation Diabetes 50 2001 1571 1579
85. F. Sanvito, P.L. Herrera, J. Huarte, A. Nichols, R. Montesano, L. Orci, and J.D. Vassalli TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro Development 120 1994 3451 3462
86. V.A. McLin, S.A. Rankin, and A.M. Zorn Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development Development 134 2007 2207 2217
87. R.S. Heller, D.S. Dichmann, J. Jensen, C. Miller, G. Wong, O.D. Madsen, and P. Serup Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation Dev Dyn 225 2002 260 270
88. J. Dessimoz, C. Bonnard, J. Huelsken, and A. Grapin-Botton Pancreas-specific deletion of beta-catenin reveals Wnt-dependent and Wnt-independent functions during development Curr Biol 15 2005 1677 1683
89. L.C. Murtaugh, A.C. Law, Y. Dor, and D.A. Melton Beta-catenin is essential for pancreatic acinar but not islet development Development 132 2005 4663 4674
90. J.M. Wells, F. Esni, G.P. Boivin, B.J. Aronow, W. Stuart, C. Combs, A. Sklenka, S.D. Leach, and A.M. Lowy Wnt/beta-catenin signaling is required for development of the exocrine pancreas BMC Dev Biol 7 2007 4
91. P.W. Heiser, J. Lau, M.M. Taketo, P.L. Herrera, and M. Hebrok Stabilization of beta-catenin impacts pancreas growth Development 133 2006 2023 2032
92. M. Malumbres, and M. Barbacid RAS oncogenes: the first 30 years Nat Rev Cancer 3 2003 459 465
93. S.L. Campbell, R. Khosravi-Far, K.L. Rossman, G.J. Clark, and C.J. Der Increasing complexity of Ras signaling Oncogene 17 1998 1395 1413
94. D.A. Tuveson, A.T. Shaw, N.A. Willis, D.P. Silver, E.L. Jackson, S. Chang, K.L. Mercer, R. Grochow, H. Hock, and D. Crowley Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects Cancer Cell 5 2004 375 387
95. G.M. Sclabas, S. Fujioka, C. Schmidt, D.B. Evans, and P.J. Chiao NF-kappaB in pancreatic cancer Int J Gastrointest Cancer 33 2003 15 26
96. C. Almoguera, D. Shibata, K. Forrester, J. Martin, N. Arnheim, and M. Perucho Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes Cell 53 1988 549 554
97. D.S. Klimstra, and D.S. Longnecker K-ras mutations in pancreatic ductal proliferative lesions Am J Pathol 145 1994 1547 1550
98. E. Rozenblum, M. Schutte, M. Goggins, S.A. Hahn, S. Panzer, M. Zahurak, S.N. Goodman, T.A. Sohn, R.H. Hruban, and C.J. Yeo Tumor-suppressive pathways in pancreatic carcinoma Cancer Res 57 1997 1731 1734
99. E.L. Jackson, N. Willis, K. Mercer, R.T. Bronson, D. Crowley, R. Montoya, T. Jacks, and D.A. Tuveson Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras Genes Dev 15 2001 3243 3248
100. S.R. Hingorani, E.F. Petricoin, A. Maitra, V. Rajapakse, C. King, M.A. Jacobetz, S. Ross, T.P. Conrads, T.D. Veenstra, and B.A. Hitt Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse Cancer Cell 4 2003 437 450
101. C.A. Moskaluk, R.H. Hruban, and S.E. Kern p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma Cancer Res 57 1997 2140 2143
102. I.B. Weinstein, and A. Joe Oncogene addiction Cancer Res 68 2008 3077 3080 discussion 3080
103. T.R. Brummelkamp, R. Bernards, and R. Agami Stable suppression of tumorigenicity by virus-mediated RNA interference Cancer Cell 2 2002 243 247
104. J.B. Fleming, G.L. Shen, S.E. Holloway, M. Davis, and R.A. Brekken Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy Mol Cancer Res 3 2005 413 423
105. T. Hirano, Y. Shino, T. Saito, F. Komoda, Y. Okutomi, A. Takeda, T. Ishihara, T. Yamaguchi, H. Saisho, and H. Shirasawa Dominant negative MEKK1 inhibits survival of pancreatic cancer cells Oncogene 21 2002 5923 5928
106. C.A. Omer, and N.E. Kohl CA1A2X-competitive inhibitors of farnesyltransferase as anti-cancer agents Trends Pharmacol Sci 18 1997 437 444
107. E. Van Cutsem, H. van de Velde, P. Karasek, H. Oettle, W.L. Vervenne, A. Szawlowski, P. Schoffski, S. Post, C. Verslype, and H. Neumann Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer J Clin Oncol 22 2004 1430 1438
108. J. Luttges, B. Schlehe, M.A. Menke, I. Vogel, D. Henne-Bruns, and G. Kloppel The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium Cancer 85 1999 1703 1710
109. C. Carriere, A.L. Young, J.R. Gunn, D.S. Longnecker, and M. Korc Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras Biochem Biophys Res Commun 382 2009 561 565
110. S.Y. Gidekel Friedlander, G.C. Chu, E.L. Snyder, N. Girnius, G. Dibelius, D. Crowley, E. Vasile, R.A. DePinho, and T. Jacks Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras Cancer Cell 16 2009 379 389
111. A.B. Lowenfels, P. Maisonneuve, G. Cavallini, R.W. Ammann, P.G. Lankisch, J.R. Andersen, E.P. Dimagno, A. Andren-Sandberg, and L. Domellof Pancreatitis and the risk of pancreatic cancer. International pancreatitis study group N Engl J Med 328 1993 1433 1437
112. R.D. Duan, C.F. Zheng, K.L. Guan, and J.A. Williams Activation of MAP kinase kinase (MEK) and Ras by cholecystokinin in rat pancreatic acini Am J Physiol 268 1995 G1060 G1065
113. B. Ji, L. Tsou, H. Wang, S. Gaiser, D.Z. Chang, J. Daniluk, Y. Bi, T. Grote, D.S. Longnecker, and C.D. Logsdon Ras activity levels control the development of pancreatic diseases Gastroenterology 137 107282 2009 e1071 e1076
114. S.R. Hustinx, L.M. Leoni, C.J. Yeo, P.N. Brown, M. Goggins, S.E. Kern, R.H. Hruban, and A. Maitra Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion Mod Pathol 18 2005 959 963
115. C.J. Sherr The INK4a/ARF network in tumour suppression Nat Rev Mol Cell Biol 2 2001 731 737
116. J. Krishnamurthy, C. Torrice, M.R. Ramsey, G.I. Kovalev, K. Al-Regaiey, L. Su, and N.E. Sharpless Ink4a/Arf expression is a biomarker of aging J Clin Invest 114 2004 1299 1307
117. N.T. van Heek, A.K. Meeker, S.E. Kern, C.J. Yeo, K.D. Lillemoe, J.L. Cameron, G.J. Offerhaus, J.L. Hicks, R.E. Wilentz, and M.G. Goggins Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia Am J Pathol 161 2002 1541 1547
118. A.M. Goldstein, M.C. Fraser, J.P. Struewing, C.J. Hussussian, K. Ranade, D.P. Zametkin, L.S. Fontaine, S.M. Organic, N.C. Dracopoli, and W.H. Clark Jr. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations N Engl J Med 333 1995 970 974
119. A.J. Whelan, D. Bartsch, and P.J. Goodfellow Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene N Engl J Med 333 1995 975 977
120. N.E. Sharpless, and R.A. DePinho Cancer: crime and punishment Nature 436 2005 636 637
121. A.J. Aguirre, N. Bardeesy, M. Sinha, L. Lopez, D.A. Tuveson, J. Horner, M.S. Redston, and R.A. DePinho Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma Genes Dev 17 2003 3112 3126
122. J. Pomerantz, N. Schreiber-Agus, N.J. Liegeois, A. Silverman, L. Alland, L. Chin, J. Potes, K. Chen, I. Orlow, and H.W. Lee The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53 Cell 92 1998 713 723
123. A. Maitra, N.V. Adsay, P. Argani, C. Iacobuzio-Donahue, A. De Marzo, J.L. Cameron, C.J. Yeo, and R.H. Hruban Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray Mod Pathol 16 2003 902 912
124. N. Bardeesy, A.J. Aguirre, G.C. Chu, K.H. Cheng, L.V. Lopez, A.F. Hezel, B. Feng, C. Brennan, R. Weissleder, and U. Mahmood Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse Proc Natl Acad Sci USA 103 2006 5947 5952
125. C.R. Boschman, S. Stryker, J.K. Reddy, and M.S. Rao Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas Am J Pathol 145 1994 1291 1295
126. T. Harada, K. Okita, K. Shiraishi, N. Kusano, T. Furuya, A. Oga, S. Kawauchi, S. Kondoh, and K. Sasaki Detection of genetic alterations in pancreatic cancers by comparative genomic hybridization coupled with tissue microdissection and degenerate oligonucleotide primed polymerase chain reaction Oncology 62 2002 251 258
127. S.A. Hahn, M. Schutte, A.T. Hoque, C.A. Moskaluk, L.T. da Costa, E. Rozenblum, C.L. Weinstein, A. Fischer, C.J. Yeo, and R.H. Hruban DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science 271 1996 350 353
128. R.E. Wilentz, C.A. Iacobuzio-Donahue, P. Argani, D.M. McCarthy, J.L. Parsons, C.J. Yeo, S.E. Kern, and R.H. Hruban Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression Cancer Res 60 2000 2002 2006
129. A.F. Baas, L. Smit, and H. Clevers LKB1 tumor suppressor protein: PARtaker in cell polarity Trends Cell Biol 14 2004 312 319
130. N. Bardeesy, M. Sinha, A.F. Hezel, S. Signoretti, N.A. Hathaway, N.E. Sharpless, M. Loda, D.R. Carrasco, and R.A. DePinho Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation Nature 419 2002 162 167
131. J.M. Lizcano, O. Goransson, R. Toth, M. Deak, N.A. Morrice, J. Boudeau, S.A. Hawley, L. Udd, T.P. Makela, and D.G. Hardie LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1 EMBO J 23 2004 833 843
132. R.J. Shaw, M. Kosmatka, N. Bardeesy, R.L. Hurley, L.A. Witters, R.A. DePinho, and L.C. Cantley The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress Proc Natl Acad Sci USA 101 2004 3329 3335
133. F.M. Giardiello, J.D. Brensinger, A.C. Tersmette, S.N. Goodman, G.M. Petersen, S.V. Booker, M. Cruz-Correa, and J.A. Offerhaus Very high risk of cancer in familial Peutz-Jeghers syndrome Gastroenterology 119 2000 1447 1453
134. F. Sahin, A. Maitra, P. Argani, N. Sato, N. Maehara, E. Montgomery, M. Goggins, R.H. Hruban, and G.H. Su Loss of Stk11/Lkb1 expression in pancreatic and biliary neoplasms Mod Pathol 16 2003 686 691
135. S. Jones, R.H. Hruban, M. Kamiyama, M. Borges, X. Zhang, D.W. Parsons, J.C. Lin, E. Palmisano, K. Brune, and E.M. Jaffee Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene Science 324 2009 217
136. E.P. Slater, P. Langer, E. Niemczyk, K. Strauch, J. Butler, N. Habbe, J. Neoptolemos, W. Greenhalf, and D.K. Bartsch PALB2 mutations in European familial pancreatic cancer families Clin Genet 5 2010 490 494
137. M.D. Tischkowitz, N. Sabbaghian, N. Hamel, A. Borgida, C. Rosner, N. Taherian, A. Srivastava, S. Holter, H. Rothenmund, and P. Ghadirian Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer Gastroenterology 137 2009 1183 1186
138. N. Rahman, S. Seal, D. Thompson, P. Kelly, A. Renwick, A. Elliott, S. Reid, K. Spanova, R. Barfoot, and T. Chagtai PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene Nat Genet 39 2007 165 167
139. R.R. McWilliams, W.R. Bamlet, M. de Andrade, D.N. Rider, F.J. Couch, J.M. Cunningham, M.E. Matsumoto, K.G. Rabe, T.J. Hammer, and G.M. Petersen Polymorphic variants in hereditary pancreatic cancer genes are not associated with pancreatic cancer risk Cancer Epidemiol Biomarkers Prev 18 2009 2549 2552
140. K.L. Pogue-Geile, R. Chen, M.P. Bronner, T. Crnogorac-Jurcevic, K.W. Moyes, S. Dowen, C.A. Otey, D.A. Crispin, R.D. George, and D.C. Whitcomb Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism PLoS Med 3 2006 e516
141. M.M. Parast, and C.A. Otey Characterization of palladin, a novel protein localized to stress fibers and cell adhesions J Cell Biol 150 2000 643 656
142. C.A. Otey, A. Rachlin, M. Moza, D. Arneman, and O. Carpen The palladin/myotilin/myopalladin family of actin-associated scaffolds Int Rev Cytol 246 2005 31 58
143. S.M. Goicoechea, B. Bednarski, C. Stack, D.W. Cowan, K. Volmar, L. Thorne, E. Cukierman, A.K. Rustgi, T. Brentnall, and R.F. Hwang Isoform-specific upregulation of palladin in human and murine pancreas tumors PLoS ONE 5 2010 e10347
144. A. Andea, F. Sarkar, and V.N. Adsay Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma Mod Pathol 16 2003 996 1006
145. A.L. Cubilla, and P.J. Fitzgerald Morphological lesions associated with human primary invasive nonendocrine pancreas cancer Cancer Res 36 1976 2690 2698
146. R.H. Hruban, N.V. Adsay, J. Albores-Saavedra, M.R. Anver, A.V. Biankin, G.P. Boivin, E.E. Furth, T. Furukawa, A. Klein, and D.S. Klimstra Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations Cancer Res 66 2006 95 106
147. R.H. Hruban, N.V. Adsay, J. Albores-Saavedra, C. Compton, E.S. Garrett, S.N. Goodman, S.E. Kern, D.S. Klimstra, G. Kloppel, and D.S. Longnecker Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions Am J Surg Pathol 25 2001 579 586
148. N.B. Prasad, A.V. Biankin, N. Fukushima, A. Maitra, S. Dhara, A.G. Elkahloun, R.H. Hruban, M. Goggins, and S.D. Leach Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells Cancer Res 65 2005 1619 1626
149. K.W. Kinzler, and B. Vogelstein Lessons from hereditary colorectal cancer Cell 87 1996 159 170
150. S.P. Thayer, M.P. di Magliano, P.W. Heiser, C.M. Nielsen, D.J. Roberts, G.Y. Lauwers, Y.P. Qi, S. Gysin, C. Fernandez-del Castillo, and V. Yajnik Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis Nature 425 2003 851 856
151. J.P. Morton, M.E. Mongeau, D.S. Klimstra, J.P. Morris, Y.C. Lee, Y. Kawaguchi, C.V. Wright, M. Hebrok, and B.C. Lewis Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis Proc Natl Acad Sci USA 104 2007 5103 5108
152. S. Jones, X. Zhang, D.W. Parsons, J.C. Lin, R.J. Leary, P. Angenendt, P. Mankoo, H. Carter, H. Kamiyama, and A. Jimeno Core signaling pathways in human pancreatic cancers revealed by global genomic analyses Science 321 2008 1801 1806
153. M. Pasca di Magliano, S. Sekine, A. Ermilov, J. Ferris, A.A. Dlugosz, and M. Hebrok Hedgehog/Ras interactions regulate early stages of pancreatic cancer Genes Dev 20 2006 3161 3173
154. J.M. Bailey, A.M. Mohr, and M.A. Hollingsworth Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer Oncogene 28 2009 3513 3525
155. G. Feldmann, S. Dhara, V. Fendrich, D. Bedja, R. Beaty, M. Mullendore, C. Karikari, H. Alvarez, C. Iacobuzio-Donahue, and A. Jimeno Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers Cancer Res 67 2007 2187 2196
156. G. Feldmann, N. Habbe, S. Dhara, S. Bisht, H. Alvarez, V. Fendrich, R. Beaty, M. Mullendore, C. Karikari, and N. Bardeesy Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer Gut 57 2008 1420 1430
157. K.P. Olive, M.A. Jacobetz, C.J. Davidson, A. Gopinathan, D. McIntyre, D. Honess, B. Madhu, M.A. Goldgraben, M.E. Caldwell, and D. Allard Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer Science 324 2009 1457 1461
158. H. Tian, C.A. Callahan, K.J. DuPree, W.C. Darbonne, C.P. Ahn, S.J. Scales, and F.J. de Sauvage Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis Proc Natl Acad Sci USA 106 2009 4254 4259
159. O. Strobel, D.E. Rosow, E.Y. Rakhlin, G.Y. Lauwers, A.G. Trainor, J. Alsina, C. Fernandez-Del Castillo, A.L. Warshaw, and S.P. Thayer Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia Gastroenterology 138 2010 1166 1177
160. O. Nolan-Stevaux, J. Lau, M.L. Truitt, G.C. Chu, M. Hebrok, M.E. Fernandez-Zapico, and D. Hanahan GLI1 is regulated through Smoothened- independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation Genes Dev 23 2009 24 36
161. K. Kuwahara, T. Sasaki, Y. Kuwada, M. Murakami, S. Yamasaki, and K. Chayama Expressions of angiogenic factors in pancreatic ductal carcinoma: a correlative study with clinicopathologic parameters and patient survival Pancreas 26 2003 344 349
162. Y. Yamanaka, H. Friess, M. Buchler, H.G. Beger, E. Uchida, M. Onda, M.S. Kobrin, and M. Korc Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage Cancer Res 53 1993 5289 5296
163. M. Kornmann, T. Ishiwata, K. Matsuda, M.E. Lopez, K. Fukahi, G. Asano, H.G. Beger, and M. Korc IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cells Gastroenterology 123 2002 301 313
164. Z. Liu, N. Neiss, S. Zhou, D. Henne-Bruns, M. Korc, M. Bachem, and M. Kornmann Identification of a fibroblast growth factor receptor 1 splice variant that inhibits pancreatic cancer cell growth Cancer Res 67 2007 2712 2719
165. M. Wagner, M.E. Lopez, M. Cahn, and M. Korc Suppression of fibroblast growth factor receptor signaling inhibits pancreatic cancer growth in vitro and in vivo Gastroenterology 114 1998 798 807
166. G. Chen, X. Tian, Z. Liu, S. Zhou, B. Schmidt, D. Henne-Bruns, M. Bachem, and M. Kornmann Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression Br J Cancer 102 2010 188 195
167. S. Nomura, H. Yoshitomi, S. Takano, T. Shida, S. Kobayashi, M. Ohtsuka, F. Kimura, H. Shimizu, H. Yoshidome, and A. Kato FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer Br J Cancer 99 2008 305 313
168. I. El-Hariry, M. Pignatelli, and N.R. Lemoine FGF-1 and FGF-2 regulate the expression of E-cadherin and catenins in pancreatic adenocarcinoma Int J Cancer 94 2001 652 661
169. C. Pistol-Tanase, E. Raducan, S.O. Dima, L. Albulescu, I. Alina, P. Marius, L.M. Cruceru, E. Codorean, T.M. Neagu, and I. Popescu Assessment of soluble angiogenic markers in pancreatic cancer Biomark Med 2 2008 447 455
170. N. Habbe, G. Shi, R.A. Meguid, V. Fendrich, F. Esni, H. Chen, G. Feldmann, D.A. Stoffers, S.F. Konieczny, and S.D. Leach Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice Proc Natl Acad Sci USA 105 2008 18913 18918
171. M.E. Mullendore, J.B. Koorstra, Y.M. Li, G.J. Offerhaus, X. Fan, C.M. Henderson, W. Matsui, C.G. Eberhart, A. Maitra, and G. Feldmann Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer Clin Cancer Res 15 2009 2291 2301
172. B.Z. Stanger, B. Stiles, G.Y. Lauwers, N. Bardeesy, M. Mendoza, Y. Wang, A. Greenwood, K.H. Cheng, M. McLaughlin, and D. Brown Pten constrains centroacinar cell expansion and malignant transformation in the pancreas Cancer Cell 8 2005 185 195
173. L. Zhu, G. Shi, C.M. Schmidt, R.H. Hruban, and S.F. Konieczny Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia Am J Pathol 171 2007 263 273
174. R. Plentz, J.S. Park, A.D. Rhim, D. Abravanel, A.F. Hezel, S.V. Sharma, S. Gurumurthy, V. Deshpande, C. Kenific, and J. Settleman Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma Gastroenterology 136 17411749 2009 e1746
175. G. Shi, L. Zhu, Y. Sun, R. Bettencourt, B. Damsz, R.H. Hruban, and S.F. Konieczny Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia Gastroenterology 136 2009 1368 1378
176. Z. Wang, Y. Li, D. Kong, S. Banerjee, A. Ahmad, A.S. Azmi, S. Ali, J.L. Abbruzzese, G.E. Gallick, and F.H. Sarkar Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway Cancer Res 69 2009 2400 2407
177. O.J. De La, L.L. Emerson, J.L. Goodman, S.C. Froebe, B.E. Illum, A.B. Curtis, and L.C. Murtaugh Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia Proc Natl Acad Sci USA 105 2008 18907 18912
178. E. Ristorcelli, and D. Lombardo Targeting Notch signaling in pancreatic cancer Expert Opin Ther Targets 14 2010 541 552
179. H. Friess, Y. Yamanaka, M. Buchler, M. Ebert, H.G. Beger, L.I. Gold, and M. Korc Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival Gastroenterology 105 1993 1846 1856
180. H. Friess, Y. Yamanaka, M. Buchler, H.G. Berger, M.S. Kobrin, R.L. Baldwin, and M. Korc 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 53 1993 2704 2707
181. M. Lohr, C. Schmidt, J. Ringel, M. Kluth, P. Muller, H. Nizze, and R. Jesnowski Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma Cancer Res 61 2001 550 555
182. J.Y. Chow, M. Ban, H.L. Wu, F. Nguyen, M. Huang, H. Chung, H. Dong, and J.M. Carethers TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells Am J Physiol Gastrointest Liver Physiol 298 2010 G275 G282
183. H.J. Maier, U. Schmidt-Strassburger, M.A. Huber, E.M. Wiedemann, H. Beug, and T. Wirth NF-kappaB promotes epithelialmesenchymal transition, migration and invasion of pancreatic carcinoma cells Cancer Lett 295 2010 214 228
184. K. Horiguchi, T. Shirakihara, A. Nakano, T. Imamura, K. Miyazono, and M. Saitoh Role of Ras signaling in the induction of snail by transforming growth factor-beta J Biol Chem 284 2009 245 253
185. N. Bardeesy, K.H. Cheng, J.H. Berger, G.C. Chu, J. Pahler, P. Olson, A.F. Hezel, J. Horner, G.Y. Lauwers, and D. Hanahan SMAD4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer Genes Dev 20 2006 3130 3146
186. H. Ijichi, A. Chytil, A.E. Gorska, M.E. Aakre, Y. Fujitani, S. Fujitani, C.V. Wright, and H.L. Moses Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression Genes Dev 20 2006 3147 3160
187. P.M. Hempen, L. Zhang, R.K. Bansal, C.A. Iacobuzio-Donahue, K.M. Murphy, A. Maitra, B. Vogelstein, R.H. Whitehead, S.D. Markowitz, and J.K. Willson Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal cancers Cancer Res 63 2003 994 999
188. B. Ryu, and S.E. Kern The essential similarity of TGFbeta and activin receptor transcriptional responses in cancer cells Cancer Biol Ther 2 2003 164 170
189. G.H. Su, R. Bansal, K.M. Murphy, E. Montgomery, C.J. Yeo, R.H. Hruban, and S.E. Kern ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma Proc Natl Acad Sci USA 98 2001 3254 3257
190. H. Ungefroren, B. Schniewind, S. Groth, W.B. Chen, S.S. Muerkoster, H. Kalthoff, and F. Fandrich Antitumor activity of ALK1 in pancreatic carcinoma cells Int J Cancer 120 2007 1641 1651
191. H. Kayed, J. Kleeff, S. Keleg, X. Jiang, R. Penzel, T. Giese, H. Zentgraf, M.W. Buchler, M. Korc, and H. Friess Correlation of glypican-1 expression with TGF-beta, BMP, and activin receptors in pancreatic ductal adenocarcinoma Int J Oncol 29 2006 1139 1148
192. L. Golkar, X.Z. Ding, M.B. Ujiki, M.R. Salabat, D.L. Kelly, D. Scholtens, A.J. Fought, D.J. Bentrem, M.S. Talamonti, and R.H. Bell Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1 J Surg Res 138 2007 163 169
193. F.H. Brembeck, A. Kaiser, K. Detjen, H. Hotz, T. Foitzik, H.J. Buhr, E.O. Riecken, and S. Rosewicz Retinoic acid receptor alpha mediates growth inhibition by retinoids in rat pancreatic carcinoma DSL-6A/C1 cells Br J Cancer 78 1998 1288 1295
194. E.O. Riecken, and S. Rosewicz Retinoids in pancreatic cancer Ann Oncol 10 Suppl 4 1999 197 200
195. S. Rosewicz, U. Stier, F. Brembeck, A. Kaiser, C.A. Papadimitriou, W.E. Berdel, B. Wiedenmann, and E.O. Riecken Retinoids: effects on growth, differentiation, and nuclear receptor expression in human pancreatic carcinoma cell lines Gastroenterology 109 1995 1646 1660
196. A.V. Perez-Castro, V.T. Tran, and M.C. Nguyen-Huu Defective lens fiber differentiation and pancreatic tumorigenesis caused by ectopic expression of the cellular retinoic acid-binding protein I Development 119 1993 363 375
197. A. Michael, M. Hill, A. Maraveyas, A. Dalgleish, and F. Lofts 13-cis-Retinoic acid in combination with gemcitabine in the treatment of locally advanced and metastatic pancreatic cancerreport of a pilot phase II study Clin Oncol (R Coll Radiol) 19 2007 150 153
198. Z.A. Rasheed, J. Yang, Q. Wang, J. Kowalski, I. Freed, C. Murter, S.M. Hong, J.B. Koorstra, N.V. Rajeshkumar, and X. He Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma J Natl Cancer Inst 102 2010 340 351
199. J.L. Dembinski, and S. Krauss Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma Clin Exp Metastasis 26 2009 611 623
200. A. Jimeno, G. Feldmann, A. Suarez-Gauthier, Z. Rasheed, A. Solomon, G.M. Zou, B. Rubio-Viqueira, E. Garcia-Garcia, F. Lopez-Rios, and W. Matsui A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development Mol Cancer Ther 8 2009 310 314
201. C.M. Barton, P.A. Hall, C.M. Hughes, W.J. Gullick, and N.R. Lemoine Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer J Pathol 163 1991 111 116
202. H. Friess, J. Kleeff, M. Korc, and M.W. Buchler Molecular aspects of pancreatic cancer and future perspectives Dig Surg 16 1999 281 290
203. M. Korc, B. Chandrasekar, Y. Yamanaka, H. Friess, M. Buchier, and H.G. Beger 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 90 1992 1352 1360
204. M. Korc Growth factors and pancreatic cancer Int J Pancreatol 9 1991 87 91
205. C.J. Bruns, M.T. Harbison, D.W. Davis, C.A. Portera, R. Tsan, D.J. McConkey, D.B. Evans, J.L. Abbruzzese, D.J. Hicklin, and R. Radinsky Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms Clin Cancer Res 6 2000 1936 1948
206. J. Li, J. Kleeff, N. Giese, M.W. Buchler, M. Korc, and H. Friess 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 2004 203 210
207. S.A. Blaine, K.C. Ray, K.M. Branch, P.S. Robinson, R.H. Whitehead, and A.L. Means Epidermal growth factor receptor regulates pancreatic fibrosis Am J Physiol Gastrointest Liver Physiol 297 2009 G434 G441
208. S.Y. Song, M. Gannon, M.K. Washington, C.R. Scoggins, I.M. Meszoely, J.R. Goldenring, C.R. Marino, E.P. Sandgren, R.J. Coffey Jr., and C.V. Wright Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in transgenic mice overexpressing transforming growth factor alpha Gastroenterology 117 1999 1416 1426
209. M. Wagner, C.K. Weber, F. Bressau, F.R. Greten, V. Stagge, M. Ebert, S.D. Leach, G. Adler, and R.M. Schmid Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells Gastroenterology 122 2002 1898 1912
210. M. Wagner, F.R. Greten, C.K. Weber, S. Koschnick, T. Mattfeldt, W. Deppert, H. Kern, G. Adler, and R.M. Schmid A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease Genes Dev 15 2001 286 293
211. A. Duffy, J. Kortmansky, G.K. Schwartz, M. Capanu, S. Puleio, B. Minsky, L. Saltz, D.P. Kelsen, and E.M. O'Reilly A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma Ann Oncol 19 2008 86 91
212. M.M. Al-Aynati, N. Radulovich, R.H. Riddell, and M.S. Tsao Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia Clin Cancer Res 10 2004 1235 1240
213. A.M. Lowy, C. Fenoglio-Preiser, O.J. Kim, J. Kordich, A. Gomez, J. Knight, L. James, and J. Groden Dysregulation of beta-catenin expression correlates with tumor differentiation in pancreatic duct adenocarcinoma Ann Surg Oncol 10 2003 284 290
214. G. Zeng, M. Germinaro, A. Micsenyi, N.K. Monga, A. Bell, A. Sood, V. Malhotra, N. Sood, V. Midda, and D.K. Monga Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma Neoplasia 8 2006 279 289
215. J.P.T. Morris, D.A. Cano, S. Sekine, S.C. Wang, and M. Hebrok Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice J Clin Invest 120 2010 508 520
216. C. Guerra, A.J. Schuhmacher, M. Canamero, P.J. Grippo, L. Verdaguer, L. Perez-Gallego, P. Dubus, E.P. Sandgren, and M. Barbacid Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice Cancer Cell 11 2007 291 302
217. S. Zhao, S. Ammanamanchi, M. Brattain, L. Cao, A. Thangasamy, J. Wang, and J.W. Freeman SMAD4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells J Biol Chem 283 2008 11293 11301
218. J.T. Siveke, C. Lubeseder-Martellato, M. Lee, P.K. Mazur, H. Nakhai, F. Radtke, and R.M. Schmid Notch signaling is required for exocrine regeneration after acute pancreatitis Gastroenterology 134 2008 544 555
219. S. Dennler, J. Andre, F. Verrecchia, and A. Mauviel Cloning of the human GLI2 Promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation J Biol Chem 284 2009 31523 31531
220. Venkitaraman A.R. Cancer susceptibility and the functions of BRCA1 and BRCA2 Cell 108 2002 171 182
221. K.M. Murphy, K.A. Brune, C. Griffin, J.E. Sollenberger, G.M. Petersen, R. Bansal, R.H. Hruban, and S.E. Kern Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17% Cancer Res 62 2002 3789 3793
222. J.M. Bailey, B.J. Swanson, T. Hamada, J.P. Eggers, P.K. Singh, T. Caffery, M.M. Ouellette, and M.A. Hollingsworth Sonic hedgehog promotes desmoplasia in pancreatic cancer Clin Cancer Res 14 2008 5995 6004