Aberrant signaling pathways in pancreatic cancer: A two compartment view

Molecular Carcinogenesis

Volumn 51, Issue 1, 2012, Pages 25-39

  Mccleary Wheeler, Angela L ^a   Mcwilliams, Robert ^a   Fernandez Zapico, Martin E ^a  

^a MAYO CLINIC   (United States)

Author keywords

Pancreatic cancer; Signaling pathways; Stroma; Therapy

Indexed keywords

CANCER GROWTH FACTOR; COLLAGEN TYPE 1; CRE RECOMBINASE; CYCLIN DEPENDENT KINASE INHIBITOR 2A; ERLOTINIB; GEMCITABINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; K RAS PROTEIN; MESSENGER RNA; NOTCH1 RECEPTOR; NOTCH2 RECEPTOR; PACLITAXEL; PROTEIN P53; SMAD2 PROTEIN; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR PDX 1; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

ARTICLE; CANCER CELL; CANCER CELL CULTURE; CANCER GROWTH; CARCINOGENESIS; CELL CYCLE PROGRESSION; CLINICAL TRIAL (TOPIC); DNA DAMAGE; GENE ACTIVATION; GENE EXPRESSION; HUMAN; IMMUNOCOMPETENT CELL; METASTASIS; NONHUMAN; ONCOGENE; PANCREAS ADENOCARCINOMA; PANCREAS CANCER; PRIORITY JOURNAL; TUMOR GROWTH; TUMOR SUPPRESSOR GENE;

ADENOCARCINOMA; CELL COMMUNICATION; CLINICAL TRIALS AS TOPIC; EPITHELIAL CELLS; GENES, P16; GENES, P53; HEDGEHOG PROTEINS; HUMANS; MOLECULAR TARGETED THERAPY; PANCREATIC NEOPLASMS; PROTO-ONCOGENE PROTEINS; RAS PROTEINS; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION; STROMAL CELLS; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEINS;

EID: 83455176708     PISSN: 08991987     EISSN: 10982744     Source Type: Journal    
DOI: 10.1002/mc.20827     Document Type: Article

References (131)

1. Gomori G. The histology of the normal and diseased pancreas. Bull NY Acad Med 1945; 21: 99-111.
2. Wharton GK. The clinical aspects of the histology and pathology of the pancreas. Can Med Assoc J 1934; 30: 148-152.
3. Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003; 3: 565-576.
4. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pancreatic intraepithelial neoplasia: A new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001; 25: 579-586.
5. Zhu L, Shi G, Schmidt CM, Hruban RH, Konieczny SF. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am J Pathol 2007; 171: 263-273.
6. Hruban RH, Maitra A, Kern SE, Goggins M. Precursors to pancreatic cancer. Gastroenterol Clin North Am 2007; 36: 831-849, vi.
7. Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol 2005; 12: 81-91.
8. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6: 2969-2972.
9. Hansel DE, Kern SE, Hruban RH. Molecular pathogenesis of pancreatic cancer. Annu Rev Genomics Hum Genet 2003; 4: 237-256.
10. Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: A star on the rise in pancreatic diseases. J Clin Invest 2007; 117: 50-59.
11. Pandol S, Edderkaoui M, Gukovsky I, Lugea A, Gukovskaya A. Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol 2009; 7: S44-S47.
12. Esposito I, Kayed H, Keleg S, et al. Tumor-suppressor function of SPARC-like protein 1/Hevin in pancreatic cancer. Neoplasia 2007; 9: 8-17.
13. Sharma S, Green KB. The pancreatic duct and its arteriovenous relationship: An underutilized aid in the diagnosis and distinction of pancreatic adenocarcinoma from pancreatic intraepithelial neoplasia. A study of 126 pancreatectomy specimens. Am J Surg Pathol 2004; 28: 613-620.
14. Esposito I, Menicagli M, Funel N, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004; 57: 630-636.
15. Schmitz-Winnenthal FH, Volk C, Z'Graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005; 65: 10079-10087.
16. von Bernstorff W, Voss M, Freichel S, et al. Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 2001; 7: 925s-932s.
17. Bachem MG, Schunemann M, Ramadani M, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005; 128: 907-921.
18. Aoyagi Y, Oda T, Kinoshita T, et al. Overexpression of TGF-beta by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer. Br J Cancer 2004; 91: 1316-1326.
19. Apte MV, Park S, Phillips PA, et al. Desmoplastic reaction in pancreatic cancer: Role of pancreatic stellate cells. Pancreas 2004; 29: 179-187.
20. Masamune A, Watanabe T, Kikuta K, Shimosegawa T. Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol 2009; 7: S48-S54.
21. Svegliati-Baroni G, De Minicis S, Marzioni M. Hepatic fibrogenesis in response to chronic liver injury: Novel insights on the role of cell-to-cell interaction and transition. Liver Int 2008; 28: 1052-1064.
22. Apte MV, Wilson JS. Mechanisms of pancreatic fibrosis. Dig Dis 2004; 22: 273-279.
23. Vonlaufen A, Phillips PA, Yang L, et al. Isolation of quiescent human pancreatic stellate cells: A promising in vitro tool for studies of human pancreatic stellate cell biology. Pancreatology 2010; 10: 434-443.
24. Vonlaufen A, Joshi S, Qu C, et al. Pancreatic stellate cells: Partners in crime with pancreatic cancer cells. Cancer Res 2008; 68: 2085-2093.
25. Xu Z, Vonlaufen A, Phillips PA, et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 2010; 177: 2585-2596.
26. Korc M. Pancreatic cancer-associated stroma production. Am J Surg 2007; 194: S84-S86.
27. Chu GC, Kimmelman AC, Hezel AF, DePinho RA. Stromal biology of pancreatic cancer. J Cell Biochem 2007; 101: 887-907.
28. Hruban RH, Maitra A, Schulick R, et al. Emerging molecular biology of pancreatic cancer. Gastrointest Cancer Res 2008; 2: S10-S15.
29. Hruban RH, van Mansfeld AD, Offerhaus GJ, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993; 143: 545-554.
30. Lemoine NR, Jain S, Hughes CM, et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 1992; 102: 230-236.
31. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000; 60: 2002-2006.
32. Lohr M, Kloppel G, Maisonneuve P, Lowenfels AB, Luttges J. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: A meta-analysis. Neoplasia 2005; 7: 17-23.
33. Leach SD. Mouse models of pancreatic cancer: The fur is finally flying. Cancer Cell 2004; 5: 7-11.
34. Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 2006; 20: 3161-3173.
35. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003; 4: 437-450.
36. Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003; 17: 3112-3126.
37. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997; 57: 3126-3130.
38. Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994; 8: 27-32.
39. Rozenblum E, Schutte M, Goggins M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997; 57: 1731-1734.
40. Wilentz RE, Geradts J, Maynard R, et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: Loss of intranuclear expression. Cancer Res 1998; 58: 4740-4744.
41. Chu GC, et al. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA 2006; 103: 5947-5952.
42. Ruggeri B, Zhang SY, Caamano J, DiRado M, Flynn SD, Klein-Szanto AJ. Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Oncogene 1992; 7: 1503-1511.
43. Huang L, Lang D, Geradts J, et al. Molecular and immunochemical analyses of RB1 and cyclin D1 in human ductal pancreatic carcinomas and cell lines. Mol Carcinog 1996; 15: 85-95.
44. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113: 685-700.
45. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321: 1801-1806.
46. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996; 271: 350-353.
47. Hahn SA, Hoque AT, Moskaluk CA, et al. Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res 1996; 56: 490-494.
48. Schutte M, Hruban RH, Hedrick L, et al. DPC4 gene in various tumor types. Cancer Res 1996; 56: 2527-2530.
49. Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009; 15: 4674-4679.
50. Ellenrieder V, Hendler SF, Boeck W, et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res 2001; 61: 4222-4228.
51. Adrian K, Strouch MJ, Zeng Q, et al. Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer. Cancer Res 2009; 69: 9169-9174.
52. Kojima K, Vickers SM, Adsay NV, et al. Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res 2007; 67: 8121-8130.
53. Izeradjene K, Combs C, Best M, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 2007; 11: 229-243.
54. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003; 425: 577-584.
55. Singh G, Singh SK, Konig A, et al. Sequential activation of NFAT and c-Myc transcription factors mediates the TGF-beta switch from a suppressor to a promoter of cancer cell proliferation. J Biol Chem 2010; 285: 27241-27250.
56. Vogelmann R, Ruf D, Wagner M, Adler G, Menke A. Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model. Am J Physiol Gastrointest Liver Physiol 2001; 280: G164-G172.
57. Bardeesy N, Cheng KH, Berger JH, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 2006; 20: 3130-3146.
58. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: Implications for pancreatic fibrogenesis. Gut 1999; 44: 534-541.
59. Haber PS, Keogh GW, Apte MV, et al. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am J Pathol 1999; 155: 1087-1095.
60. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 1994; 54: 3025-3033.
61. Scarpa A, Capelli P, Mukai K, et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol 1993; 142: 1534-1543.
62. Barton CM, Staddon SL, Hughes CM, et al. Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer 1991; 64: 1076-1082.
63. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7: 469-483.
64. Wagner M, Greten FR, Weber CK, et al. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev 2001; 15: 286-293.
65. DiGiuseppe JA, Hruban RH, Goodman SN, et al. Overexpression of p53 protein in adenocarcinoma of the pancreas. Am J Clin Pathol 1994; 101: 684-688.
66. Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425: 851-856.
67. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003; 425: 846-851.
68. Nolan-Stevaux O, Lau J, Truitt ML, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009; 23: 24-36.
69. Dennler S, Andre J, Alexaki I, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res 2007; 67: 6981-6986.
70. Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008; 455: 406-410.
71. Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 2009; 106: 4254-4259.
72. Bailey JM, Swanson BJ, Hamada T, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 2008; 14: 5995-6004.
73. Walter K, Omura N, Hong SM, et al. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin Cancer Res 2010; 16: 1781-1789.
74. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457-1461.
75. Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature 1999; 400: 877-881.
76. Su Y, Buchler P, Gazdhar A, et al. Pancreatic regeneration in chronic pancreatitis requires activation of the notch signaling pathway. J Gastrointest Surg 2006; 10: 1230-1241 (discussion 1242).
77. Mullendore ME, Koorstra JB, Li YM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res 2009; 15: 2291-2301.
78. Wang Z, Banerjee S, Li Y, Rahman KM, Zhang Y, Sarkar FH. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 2006; 66: 2778-2784.
79. Mazur PK, Einwachter H, Lee M, et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA 2010; 107: 13438-13443.
80. Plentz R, Park JS, Rhim AD, et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 2009; 136: 1741-1749, e1746.
81. Zeng G, Germinaro M, Micsenyi A, et al. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006; 8: 279-289.
82. Pasca di Magliano M, Biankin AV, Heiser PW, et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One 2007; 2: e1155.
83. Lowy AM, Fenoglio-Preiser C, Kim OJ, et al. Dysregulation of beta-catenin expression correlates with tumor differentiation in pancreatic duct adenocarcinoma. Ann Surg Oncol 2003; 10: 284-290.
84. Morris JPt, Cano DA, Sekine S, Wang SC, Hebrok M. Beta-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest 2010; 120: 508-520.
85. Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD. Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2007; 2: e392.
86. Iacobuzio-Donahue CA, Maitra A, Olsen M, et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol 2003; 162: 1151-1162.
87. Su AI, Welsh JB, Sapinoso LM, et al. Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001; 61: 7388-7393.
88. Li J, Kleeff J, Abiatari I, et al. Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer. Mol Cancer 2005; 4: 14.
89. Williams TM, Weiner DB, Greene MI, Maguire HC, Jr. Expression of c-erbB-2 in human pancreatic adenocarcinomas. Pathobiology 1991; 59: 46-52.
90. Satoh K, Sasano H, Shimosegawa T, et al. An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin-hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer 1993; 72: 51-56.
91. Day JD, Digiuseppe JA, Yeo C, et al. Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol 1996; 27: 119-124.
92. Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchier M, Beger HG. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 1992; 90: 1352-1360.
93. Wagner M, Weber CK, Bressau F, et al. Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells. Gastroenterology 2002; 122: 1898-1912.
94. Siveke JT, Einwachter H, Sipos B, Lubeseder-Martellato C, Kloppel G, Schmid RM. Concomitant pancreatic activation of Kras(G12D) and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer Cell 2007; 12: 266-279.
95. Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res 1995; 1: 1413-1420.
96. Blaine SA, Ray KC, Branch KM, Robinson PS, Whitehead RH, Means AL. Epidermal growth factor receptor regulates pancreatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2009; 297: G434-G441.
97. Zhang Z, Rigas B. NF-kappaB, inflammation and pancreatic carcinogenesis: NF-kappaB as a chemoprevention target (review). Int J Oncol 2006; 29: 185-192.
98. Whitcomb DC. Inflammation Cancer V. Chronic pancreatitis and pancreatic cancer. Am J Physiol Gastrointest Liver Physiol 2004; 287: G315-G319.
99. Malka D, Hammel P, Maire F, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002; 51: 849-852.
100. Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM. NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology 1999; 116: 420-430.
101. Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5: 119-127.
102. Chandler NM, Canete JJ, Callery MP. Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J Surg Res 2004; 118: 9-14.
103. Fujioka S, Sclabas GM, Schmidt C, et al. Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 2003; 9: 346-354.
104. Fujioka S, Sclabas GM, Schmidt C, et al. Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. Oncogene 2003; 22: 1365-1370.
105. Ougolkov AV, Fernandez-Zapico ME, Savoy DN, Urrutia RA, Billadeau DD. Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 2005; 65: 2076-2081.
106. Evan GI, Littlewood TD. The role of c-myc in cell growth. Curr Opin Genet Dev 1993; 3: 44-49.
107. Adhikary S, Eilers M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 2005; 6: 635-645.
108. Land H, Parada LF, Weinberg RA. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 1983; 304: 596-602.
109. Sandgren EP, Quaife CJ, Paulovich AG, Palmiter RD, Brinster RL. Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci USA 1991; 88: 93-97.
110. Sandgren EP, Luetteke NC, Qiu TH, Palmiter RD, Brinster RL, Lee DC. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 1993; 13: 320-330.
111. Schaeffer BK, Terhune PG, Longnecker DS. Pancreatic carcinomas of acinar and mixed acinar/ductal phenotypes in Ela-1-myc transgenic mice do not contain c-K-ras mutations. Am J Pathol 1994; 145: 696-701.
112. Schleger C, Verbeke C, Hildenbrand R, Zentgraf H, Bleyl U. c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: Incidence, mechanisms, and clinical significance. Mod Pathol 2002; 15: 462-469.
113. Buchholz M, Schatz A, Wagner M, et al. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J 2006; 25: 3714-3724.
114. Koenig A, Linhart T, Schlengemann K, et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology 2010; 138: 1189-1199, e1181-e1182.
115. Kita K, Saito S, Morioka CY, Watanabe A. Growth inhibition of human pancreatic cancer cell lines by anti-sense oligonucleotides specific to mutated K-ras genes. Int J Cancer 1999; 80: 553-558.
116. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 1999; 17: 3631-3652.
117. Van Cutsem E, van de Velde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22: 1430-1438.
118. Fleming JB, Shen GL, Holloway SE, Davis M, Brekken RA. Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: Justification for K-ras-directed therapy. Mol Cancer Res 2005; 3: 413-423.
119. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials. J Clin Oncol 2007; 25: 1960-1966.
120. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626-1634.
121. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 26: 5705-5712.
122. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-7109.
123. Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem 2007; 282: 14048-14055.
124. Truty MJ, Urrutia R. Basics of TGF-beta and pancreatic cancer. Pancreatology 2007; 7: 423-435.
125. Tascilar M, Skinner HG, Rosty C, et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 2001; 7: 4115-4121.
126. Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L. Rational targeting of Notch signaling in cancer. Oncogene 2008; 27: 5124-5131.
127. Park SS, Eom YW, Kim EH, et al. Involvement of c-Src kinase in the regulation of TGF-beta1-induced apoptosis. Oncogene 2004; 23: 6272-6281.
128. Lane TF, Sage EH. The biology of SPARC, a protein that modulates cell-matrix interactions. FASEB J 1994; 8: 163-173.
129. Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007; 25: 319-325.
130. Mantoni TS, Schendel RR, Rodel F, et al. Stromal SPARC expression and patient survival after chemoradiation for non-resectable pancreatic adenocarcinoma. Cancer Biol Ther 2008; 7: 1806-1815.
131. Guweidhi A, Kleeff J, Adwan H, et al. Osteonectin influences growth and invasion of pancreatic cancer cells. Ann Surg 2005; 242: 224-234.