Advertisement

Molecular Relationships Between Chronic Pancreatitis and Cancer

  • Craig D. Logsdon
  • Baoan Ji
  • Rosa F. Hwang
Reference work entry

Abstract:

Chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) have long been known to be related diseases of the exocrine pancreas, however much of the existing literature is focused on identifying the differences between these two diseases. Thus, the exact nature of the relationship between CP and PDAC is unclear. CP is a major risk factor for PDAC, but the mechanisms of the increased risk have not been well characterized. PDAC is always associated with areas of histological CP, but whether CP is a cause, a precursor or a consequence of PDAC is unknown. Recently, novel mouse models of PDAC and CP have been developed that are providing new insights into these relationships. Moreover, the most obvious connection between CP and PDAC is the common characteristic of a prominent desmoplastic stroma. It is now understood that this stroma is the product of pancreatic stellate cells. New information about the function and regulation of these cells provides new insights into the relationships between these diseases. Clearly there is much to learn by considering the similarities between CP and PDAC, rather than continuing to focus on differences.

Keywords

Pancreatic Cancer Chronic Pancreatitis Acinar Cell Pancreatic Cancer Cell Connective Tissue Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Mortenson MM, Katz MH, Tamm EP, Bhutani MS, Wang H, Evans DB, Fleming JB: Current diagnosis and management of unusual pancreatic tumors. Am J Surg 2008;196:100–113.PubMedCrossRefGoogle Scholar
  2. 2.
    Degen L, Wiesner W, Beglinger C: Cystic and solid lesions of the pancreas. Best Pract Res Clin Gastroenterol 2008;22:91–103.PubMedCrossRefGoogle Scholar
  3. 3.
    Maitra A, Hruban RH: Pancreatic cancer. Annu Rev Pathol 2008;3:157–188.PubMedCrossRefGoogle Scholar
  4. 4.
    Hart AR, Kennedy H, Harvey I: Pancreatic cancer: a review of the evidence on causation. Clin Gastroenterol Hepatol 2008;6:275–282.PubMedCrossRefGoogle Scholar
  5. 5.
    Koliopanos A, Avgerinos C, Paraskeva C, Touloumis Z, Kelgiorgi D, Dervenis C: Molecular aspects of carcinogenesis in pancreatic cancer. Hepatobiliary Pancreat Dis Int 2008;7:345–356.PubMedGoogle Scholar
  6. 6.
    Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, DePinho RA: Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20:1218–1249.PubMedCrossRefGoogle Scholar
  7. 7.
    Brembeck FH, Schreiber FS, Deramaudt TB, Craig L, Rhoades B, Swain G, Grippo P, Stoffers DA, Silberg DG, Rustgi AK: The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res 2003;63:2005–2009.PubMedGoogle Scholar
  8. 8.
    Grippo PJ, Nowlin PS, Demeure MJ, Longnecker DS, Sandgren EP: Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res 2003;63:2016–2019.PubMedGoogle Scholar
  9. 9.
    Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, Dubus P, Sandgren EP, Barbacid M: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007;11:291–302.PubMedCrossRefGoogle Scholar
  10. 10.
    Pour PM, Pandey KK, Batra SK: What is the origin of pancreatic adenocarcinoma? Mol Cancer 2003;2:13.PubMedCrossRefGoogle Scholar
  11. 11.
    Stanger BZ, Stiles B, Lauwers GY, Bardeesy N, Mendoza M, Wang Y, Greenwood A, Cheng KH, McLaughlin M, Brown D, et al.: Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 2005;8:185–195.PubMedCrossRefGoogle Scholar
  12. 12.
    Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, et al.: Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437–450.PubMedCrossRefGoogle Scholar
  13. 13.
    Carriere C, Seeley ES, Goetze T, Longnecker DS, Korc M: The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia. Proc Natl Acad Sci USA 2007;104:4437–4442.PubMedCrossRefGoogle Scholar
  14. 14.
    Otsuki M: Chronic pancreatitis. The problems of diagnostic criteria. Pancreatology 2004;4:28–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Witt H, Apte MV, Keim V, Wilson JS: Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 2007;132:1557–1573.PubMedCrossRefGoogle Scholar
  16. 16.
    Steer ML, Waxman I, Freedman S: Chronic pancreatitis. N Engl J Med 1995;332:1482–1490.PubMedCrossRefGoogle Scholar
  17. 17.
    Seymour AB, Hruban RH, Redston M, Caldas C, Powell SM, Kinzler KW, Yeo CJ, Kern SE: Allelotype of Pancreatic Adenocarcinoma. Cancer res 1994;2761–2764.Google Scholar
  18. 18.
    Mutema G, Fenoglio-Preiser C: Pathology and Natural History of Pancreatic Cancer. In Gastrointestinal Oncology. JL Abbruzzese, (ed.). 2004; New York: Oxford University Press.Google Scholar
  19. 19.
    Ekbom A, McLaughlin JK, Karlsson BM, Nyren O, Gridley G, Adami HO, Fraumeni JF, Jr.: Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst 1994;86:625–627.PubMedCrossRefGoogle Scholar
  20. 20.
    Malka D, Hammel P, Maire F, Rufat P, Madeira I, Pessione F, Levy P, Ruszniewski P: Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002;51:849–852.PubMedCrossRefGoogle Scholar
  21. 21.
    Bansal P, Sonnenberg A: Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology 1995;109:247–251.PubMedCrossRefGoogle Scholar
  22. 22.
    Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L: Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328:1433–1437.PubMedCrossRefGoogle Scholar
  23. 23.
    Whitcomb DC: Inflammation and Cancer V. Chronic pancreatitis and pancreatic cancer. Am J Physiol Gastrointest Liver Physiol 2004;287:G315–G319.PubMedCrossRefGoogle Scholar
  24. 24.
    Lowenfels AB, Maisonneuve P: Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20:197–209.PubMedCrossRefGoogle Scholar
  25. 25.
    Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Jr., Amann ST, Toskes PP, et al.: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14:141–145.PubMedCrossRefGoogle Scholar
  26. 26.
    Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK, Jr., Perrault J, Whitcomb DC: Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442–446.PubMedCrossRefGoogle Scholar
  27. 27.
    Takaori K, Hruban RH, Maitra A, Tanigawa N: Current topics on precursors to pancreatic cancer. Adv Med Sci 2006;51:23–30.PubMedGoogle Scholar
  28. 28.
    Maitra A, Fukushima N, Takaori K, Hruban RH: Precursors to invasive pancreatic cancer. Adv Anat Pathol 2005;12:81–91.PubMedCrossRefGoogle Scholar
  29. 29.
    Hruban RH, Adsay NV, bores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Kloppel G, Longnecker DS, et al.: Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001;25:579–586.PubMedCrossRefGoogle Scholar
  30. 30.
    Feldmann G, Beaty R, Hruban RH, Maitra A: Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg 2007;14:224–232.PubMedCrossRefGoogle Scholar
  31. 31.
    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60:2002–2006.PubMedGoogle Scholar
  32. 32.
    Hruban RH, Goggins M, Parsons J, Kern SE: Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969–2972.PubMedGoogle Scholar
  33. 33.
    Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M: p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol 2003;27:1495–1501.PubMedCrossRefGoogle Scholar
  34. 34.
    Volkholz H, Stolte M, Becker V: Epithelial dysplasias in chronic pancreatitis. Virchows Arch A Pathol Anat Histol 1982;396:331–349.PubMedCrossRefGoogle Scholar
  35. 35.
    Hermanova M, Nenutil R, Kren L, Feit J, Pavlovsky Z, Dite P: Proliferative activity in pancreatic intraepithelial neoplasias of chronic pancreatitis resection specimens: detection of a high-risk lesion. Neoplasma 2004;51:400–404.PubMedGoogle Scholar
  36. 36.
    Fukushima N, Koopmann J, Sato N, Prasad N, Carvalho R, Leach SD, Hruban RH, Goggins M: Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma. Mod Pathol 2005;18:779–787.PubMedCrossRefGoogle Scholar
  37. 37.
    Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000;100:57–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al.: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801–1806.PubMedCrossRefGoogle Scholar
  39. 39.
    Saif MW, Karapanagiotou L, Syrigos K: Genetic alterations in pancreatic cancer. World J Gastroenterol 2007;13:4423–4430.PubMedGoogle Scholar
  40. 40.
    Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M: Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549–554.PubMedCrossRefGoogle Scholar
  41. 41.
    Ren YX, Xu GM, Li ZS, Song YG: Detection of point mutation in K-ras oncogene at codon 12 in pancreatic diseases. World J Gastroenterol 2004;10:881–884.PubMedGoogle Scholar
  42. 42.
    Sawada Y, Gonda H, Hayashida Y: Combined use of brushing cytology and endoscopic retrograde pancreatography for the early detection of pancreatic cancer. Acta Cytol 1989;33:870–874.PubMedGoogle Scholar
  43. 43.
    Kubota Y, Takaoka M, Tani K, Ogura M, Kin H, Fujimura K, Mizuno T, Inoue K: Endoscopic transpapillary biopsy for diagnosis of patients with pancreaticobiliary ductal strictures. Am J Gastroenterol 1993;88:1700–1704.PubMedGoogle Scholar
  44. 44.
    Arvanitakis M, Van Laethem JL, Parma J, De Maertelaer V, Delhaye M, Deviere J: Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with K-ras gene mutation. Endoscopy 2004;36:535–542.PubMedCrossRefGoogle Scholar
  45. 45.
    Shi C, Fukushima N, Abe T, Bian Y, Hua L, Wendelburg BJ, Yeo CJ, Hruban RH, Goggins MG, Eshleman JR: Sensitive and quantitative detection of KRAS2 gene mutations in pancreatic duct juice differentiates patients with pancreatic cancer from chronic pancreatitis, potential for early detection. Cancer Biol Ther 2008;7:353–360.PubMedCrossRefGoogle Scholar
  46. 46.
    Tateishi K, Tada M, Yamagata M, Isayama H, Komatsu Y, Kawabe T, Shiratori Y, Omata M: High proportion of mutant K-ras gene in pancreatic juice of patients with pancreatic cystic lesions. Gut 1999;45:737–740.PubMedCrossRefGoogle Scholar
  47. 47.
    Costentin L, Pages P, Bouisson M, Berthelemy P, Buscail L, Escourrou J, Pradayrol L, Vaysse N: Frequent deletions of tumor suppressor genes in pure pancreatic juice from patients with tumoral or nontumoral pancreatic diseases. Pancreatology 2002;2:17–25.PubMedCrossRefGoogle Scholar
  48. 48.
    Furuya N, Kawa S, Akamatsu T, Furihata K: Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice. Gastroenterology 1997;113:593–598.PubMedCrossRefGoogle Scholar
  49. 49.
    Gutierrez AA, Martinez F, Mas-Oliva J: Identification of K-ras mutations in pancreatic juice. Ann Intern Med 1996;124:1014–1015.PubMedGoogle Scholar
  50. 50.
    Kimura W, Zhao B, Futakawa N, Muto T, Makuuchi M: Significance of K-ras codon 12 point mutation in pancreatic juice in the diagnosis of carcinoma of the pancreas. Hepatogastroenterology 1999;46:532–539.PubMedGoogle Scholar
  51. 51.
    Tada M, Omata M, Kawai S, Saisho H, Ohto M, Saiki RK, Sninsky JJ: Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 1993;53:2472–2474.PubMedGoogle Scholar
  52. 52.
    Mulcahy H, Farthing MJ: Diagnosis of pancreatico-biliary malignancy: detection of gene mutations in plasma and stool. Ann Oncol 1999;10:Suppl 4:114–117.PubMedCrossRefGoogle Scholar
  53. 53.
    Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SE: Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 1994;54:3568–3573.PubMedGoogle Scholar
  54. 54.
    Wu X, Lu XH, Xu T, Qian JM, Zhao P, Guo XZ, Yang XO, Jiang WJ: Evaluation of the diagnostic value of serum tumor markers, and fecal k-ras and p53 gene mutations for pancreatic cancer. Chin J Dig Dis 2006;7:170–174.PubMedCrossRefGoogle Scholar
  55. 55.
    Lohr M, Maisonneuve P, Lowenfels AB: K-Ras mutations and benign pancreatic disease. Int J Pancreatol 2000;27:93–103.PubMedCrossRefGoogle Scholar
  56. 56.
    Berthelemy P, Bouisson M, Escourrou J, Vaysse N, Rumeau JL, Pradayrol L: Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann Intern Med 1995;123:188–191.PubMedGoogle Scholar
  57. 57.
    Hsiang D, Friess H, Buchler MW, Ebert M, Butler J, Korc M: Absence of K-ras mutations in the pancreatic parenchyma of patients with chronic pancreatitis. Am J Surg 1997;174:242–246.PubMedCrossRefGoogle Scholar
  58. 58.
    Nakaizumi A, Uehara H, Takenaka A, Uedo N, Sakai N, Yano H, Ohigashi H, Ishikawa O, Ishiguro S, Sugano K, et al.: Diagnosis of pancreatic cancer by cytology and measurement of oncogene and tumor markers in pure pancreatic juice aspirated by endoscopy. Hepatogastroenterology 1999;46:31–37.PubMedGoogle Scholar
  59. 59.
    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.PubMedCrossRefGoogle Scholar
  60. 60.
    Deramaudt T, Rustgi AK: Mutant KRAS in the initiation of pancreatic cancer. Biochim Biophys Acta 2005;1756:97–101.PubMedGoogle Scholar
  61. 61.
    Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE: Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod Pathol 2002;15:441–447.PubMedCrossRefGoogle Scholar
  62. 62.
    Klimstra DS, Longnecker DS: K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 1994;145:1547–1550.PubMedGoogle Scholar
  63. 63.
    Andea A, Sarkar F, Adsay VN: Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma. Mod Pathol 2003;16:996–1006.PubMedCrossRefGoogle Scholar
  64. 64.
    Ji B, Song J, Tsou L, Logsdon CD: Activation of K-RAS in pancreatic acinar cells causess chronic pancreatitis in transgenic mice. Gastroenterology 2007;132:A116–A117.Google Scholar
  65. 65.
    Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, et al.: Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997;57:3126–3130.PubMedGoogle Scholar
  66. 66.
    Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, Thiele HG, Honold G, Pantel K, Riethmuller G, et al.: p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene 1993;8:289–298.PubMedGoogle Scholar
  67. 67.
    Bian Y, Matsubayashi H, Li CP, Abe T, Canto M, Murphy KM, Goggins M: Detecting low-abundance p16 and p53 mutations in pancreatic juice using a novel assay: heteroduplex analysis of limiting dilution PCRs. Cancer Biol Ther 2006;5:1392–1399.PubMedGoogle Scholar
  68. 68.
    Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowskal H, Strzelczyk J, Janiak A, Malecka-Panas E: Comparative evaluation of p53 mutation in pancreatic adenocarcinoma and chronic pancreatitis. Hepatogastroenterology 2006;53:608–612.PubMedGoogle Scholar
  69. 69.
    Bhardwaj A, Marsh WL, Jr., Nash JW, Barbacioru CC, Jones S, Frankel WL: Double immunohistochemical staining with MUC4/p53 is useful in the distinction of pancreatic adenocarcinoma from chronic pancreatitis: a tissue microarray-based study. Arch Pathol Lab Med 2007;131:556–562.PubMedGoogle Scholar
  70. 70.
    Itoi T, Takei K, Sofuni A, Itokawa F, Tsuchiya T, Kurihara T, Nakamura K, Moriyasu F, Tsuchida A, Kasuya K: Immunohistochemical analysis of p53 and MIB-1 in tissue specimens obtained from endoscopic ultrasonography-guided fine needle aspiration biopsy for the diagnosis of solid pancreatic masses. Oncol Rep 2005;13:229–234.PubMedGoogle Scholar
  71. 71.
    Truty MJ, Urrutia R: Basics of TGF-beta and pancreatic cancer. Pancreatology 2007;7:423–435.PubMedCrossRefGoogle Scholar
  72. 72.
    Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, et al.: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–353.PubMedCrossRefGoogle Scholar
  73. 73.
    Biankin AV, Kench JG, Biankin SA, Lee CS, Morey AL, Dijkman FP, Coleman MJ, Sutherland RL, Henshall SM: Pancreatic intraepithelial neoplasia in association with intraductal papillary mucinous neoplasms of the pancreas: implications for disease progression and recurrence. Am J Surg Pathol 2004;28:1184–1192.PubMedCrossRefGoogle Scholar
  74. 74.
    Salek C, Benesova L, Zavoral M, Nosek V, Kasperova L, Ryska M, Strnad R, Traboulsi E, Minarik M: Evaluation of clinical relevance of examining K-ras, p16 and p53 mutations along with allelic losses at 9p and 18q in EUS-guided fine needle aspiration samples of patients with chronic pancreatitis and pancreatic cancer. World J Gastroenterol 2007;13:3714–3720.PubMedGoogle Scholar
  75. 75.
    Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark EB: Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004;239:763–769.PubMedCrossRefGoogle Scholar
  76. 76.
    Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, Misek DE, Hanash S: Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res. 2003;63:2649–2657.PubMedGoogle Scholar
  77. 77.
    Binkley CE, Zhang L, Greenson JK, Giordano TJ, Kuick R, Misek D, Hanash S, Logsdon CD, Simeone DM: The molecular basis of pancreatic fibrosis: common stromal gene expression in chronic pancreatitis and pancreatic adenocarcinoma. Pancreas 2004;29:254–263.PubMedCrossRefGoogle Scholar
  78. 78.
    Crnogorac-Jurcevic T, Efthimiou E, Nielsen T, Loader J, Terris B, Stamp G, Baron A, Scarpa A, Lemoine NR: Expression profiling of microdissected pancreatic adenocarcinomas. Oncogene 2002;21:4587–4594.PubMedCrossRefGoogle Scholar
  79. 79.
    Nakamura T, Furukawa Y, Nakagawa H, Tsunoda T, Ohigashi H, Murata K, Ishikawa O, Ohgaki K, Kashimura N, Miyamoto M, et al.: 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 2004;23:2385–2400.PubMedCrossRefGoogle Scholar
  80. 80.
    Grutzmann R, Pilarsky C, Ammerpohl O, Luttges J, Bohme A, Sipos B, Foerder M, Alldinger I, Jahnke B, Schackert HK, et al.: Gene expression profiling of microdissected pancreatic ductal carcinomas using high-density DNA microarrays. Neoplasia 2004;6:611–622.PubMedCrossRefGoogle Scholar
  81. 81.
    Alldinger I, Dittert D, Peiper M, Fusco A, Chiappetta G, Staub E, Lohr M, Jesnowski R, Baretton G, Ockert D, et al.: Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer. Pancreatology 2005;5:370–379.PubMedCrossRefGoogle Scholar
  82. 82.
    Missiaglia E, Blaveri E, Terris B, Wang YH, Costello E, Neoptolemos JP, Crnogorac-Jurcevic T, Lemoine NR: Analysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasis. Int J Cancer 2004;112:100–112.PubMedCrossRefGoogle Scholar
  83. 83.
    Domagk D, Schaefer KL, Eisenacher M, Braun Y, Wai DH, Schleicher C, Diallo-Danebrock R, Bojar H, Roeder G, Gabbert HE, et al.: Expression analysis of pancreatic cancer cell lines reveals association of enhanced gene transcription and genomic amplifications at the 8q22.1 and 8q24.22 loci. Oncol Rep 2007;17:399–407.PubMedGoogle Scholar
  84. 84.
    Archer H, Jura N, Keller J, Jacobson M, Bar-Sagi D: A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology 2006;131:1844–1855.PubMedCrossRefGoogle Scholar
  85. 85.
    Colby JK, Klein RD, McArthur MJ, Conti CJ, Kiguchi K, Kawamoto T, Riggs PK, Pavone AI, Sawicki J, Fischer SM: Progressive metaplastic and dysplastic changes in mouse pancreas induced by cyclooxygenase-2 overexpression. Neoplasia 2008;10:782–796.PubMedGoogle Scholar
  86. 86.
    Muller-Decker K, Furstenberger G, Annan N, Kucher D, Pohl-Arnold A, Steinbauer B, Esposito I, Chiblak S, Friess H, Schirmacher P, et al.: Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice. Gastroenterology 2006;130:2165–2178.PubMedCrossRefGoogle Scholar
  87. 87.
    Harris RE: Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell Biochem 2007;42:93–126.PubMedCrossRefGoogle Scholar
  88. 88.
    Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA: Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003;17:3112–3126.PubMedCrossRefGoogle Scholar
  89. 89.
    Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T: Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111–1116.PubMedCrossRefGoogle Scholar
  90. 90.
    Duan RD, Zheng CF, Guan KL, Williams JA: Activation of MAP kinase kinase (MEK) and Ras by cholecystokinin in rat pancreatic acini. Am J Physiol 1995;268:G1060–G1065.PubMedGoogle Scholar
  91. 91.
    Wagner M, Greten FR, Weber CK, Koschnick S, Mattfeldt T, Deppert W, Kern H, Adler G, Schmid RM: A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev 2001;15:286–293.PubMedCrossRefGoogle Scholar
  92. 92.
    Pandol SJ, Gukovsky I, Satoh A, Lugea A, Gukovskaya AS: Animal and in vitro models of alcoholic pancreatitis: role of cholecystokinin. Pancreas 2003;27:297–300.PubMedCrossRefGoogle Scholar
  93. 93.
    Blomhoff R, Wake K: Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J 1991;5:271–277.PubMedGoogle Scholar
  94. 94.
    Gressner A, Bachem M: Molecular mechanisms of liver fibrogenesis – a homage to the role of activated fat-storing cells. Digestion 1995;56:335–346.PubMedCrossRefGoogle Scholar
  95. 95.
    de Leeuw A, McCarthy S, Geerts A, Knook D: Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology 1984;4:392–403.PubMedCrossRefGoogle Scholar
  96. 96.
    Pinzani M: Novel insights into the biology and physiology of the Ito cell. Pharmacol Ther 1995;66:387–412.PubMedCrossRefGoogle Scholar
  97. 97.
    Apte M, Haber P, Applegate T, Norton I, McCaughan G, Korsten M, Pirola R, Wilson J: Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998;43:128–133.PubMedCrossRefGoogle Scholar
  98. 98.
    Bachem MG, Schneider E, Grob H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G: Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998;115:421–432.PubMedCrossRefGoogle Scholar
  99. 99.
    Apte M, Phillips PA, Fahmy R, Darby S, Rodgers S, McGaughan G, Korsten M, Pirola R, Naidoo D, Wilson J: Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 2000;118:780–794.PubMedCrossRefGoogle Scholar
  100. 100.
    McCarroll J, Phillips P, Santucci N, Pirola R, Wilson J, Apte M: Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis.2005.Google Scholar
  101. 101.
    Apte M, Haber P, Darby S, Rodgers S, McCaughan G, Korsten M, Pirola R, Wilson J: Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 1999;44:534–541.PubMedCrossRefGoogle Scholar
  102. 102.
    Phillips PA, McCarroll JA, Park S, Wu M-J, Pirola R, Korsten M, Wilson JS, Apte MV: Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover. Gut 2003;52:275–282.PubMedCrossRefGoogle Scholar
  103. 103.
    Gomez JA, Molero X, Vaquero E, Alonso A, Salas A, Malagelada JR: Vitamin E attenuates biochemical and morphological features associated with development of chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2004;287:G162–169.PubMedCrossRefGoogle Scholar
  104. 104.
    Yoo B, Oh T, Kim Y, Yeo M, Lee J, Surh Y, Ahn B, Kim W, Sohn S, Kim J, et al.: Novel antioxidant ameliorates the fibrosis and inflammation of cerulein-induced chronic pancreatitis in a mouse model. Pancreatology 2005;5:165–176.PubMedCrossRefGoogle Scholar
  105. 105.
    Hisada S, Shimizu K, Shiratori K, Kobayashi M: Peroxisome proliferator-activated receptor gamma ligand prevents the development of chronic pancreatitis through modulating NF-kappaB-dependent proinflammatory cytokine production and pancreatic stellate cell activation. Rocz Akad Med Bialymst 2005;50:142–147.PubMedGoogle Scholar
  106. 106.
    Apte M, Park S, Phillips P, Santucci N, Goldstein D, Kumar R, Ramm G, Buchler MW, Friess H, McCarroll J, et al.: Desmoplastic reaction in pancreatic cancer. Role of pancreatic stellate cells. Pancreas 2004;29:179–187.PubMedCrossRefGoogle Scholar
  107. 107.
    Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 2006;6:392–401.PubMedCrossRefGoogle Scholar
  108. 108.
    Mackie EJ, Chiquet-Ehrismann R, Pearson CA, Inaguma Y, Taya K, Kawarada Y, Sakakura T: Tenascin is a stromal marker for epithelial malignancy in the mammary gland. Proc Natl Acad Sci USA 1987;84:4621–4625.PubMedCrossRefGoogle Scholar
  109. 109.
    Ishihara A, Yoshida T, Tamaki H, Sakakura T: Tenascin expression in cancer cells and stroma of human breast cancer and its prognostic significance. Clin Cancer Res 1995;1:1035–1041.PubMedGoogle Scholar
  110. 110.
    Brunner A, Mayerl C, Tzankov A, Verdorfer I, Tschorner I, Rogatsch H, Mikuz G: Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer. J Clin Pathol 2004;57:927–931.PubMedCrossRefGoogle Scholar
  111. 111.
    Orimo A, Gupta P, Sgroi D, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey V, Richardson A, Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005;121:335–348.PubMedCrossRefGoogle Scholar
  112. 112.
    Olumi Af, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR: Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59:5002–5011.PubMedGoogle Scholar
  113. 113.
    Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos K, Rivera A, Ji B, Evans DB, Logsdon C: Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 2008;68:918–926.PubMedCrossRefGoogle Scholar
  114. 114.
    Yoshida S, Yokota T, Ujiki M, Ding X-Z, Pelham C, Adrian TE, Talamonti MS, Bell Jr RH, Denham W: Pancreatic cancer stimulates pancreatic stellate cell proliferation and TIMP-1 production through the MAP kinase pathway. Biochem Biophy Res Comm 2004;323:1241–1245.CrossRefGoogle Scholar
  115. 115.
    Koninger J, Giese T, di Mola FF, Wente MN, Esposito I, Bachem MG, Giese NA, Buchler MW, Friess H: Pancreatic tumor cells influence the composition of the extracellular matrix. Biochem Biophy Res Comm 2004;322:943–949.CrossRefGoogle Scholar
  116. 116.
    Bachem M, Schunemann M, Ramadani M, Siech M, Beger H, Buck A, Zhou S, Schmid-Kotsas A, Adler G: Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128:907–921.PubMedCrossRefGoogle Scholar
  117. 117.
    Lee M, Gu D, Feng L, Curriden S, Amush M, Krahl T, Gurushanthaiah D, Wilson C, Loskutoff D, Fox H, et al.: Accumulation of extracellular matrix and developmental dysregulation in the pancreas by trnasgenic produciton of transforming growth factor-B1. Am J Path 1995;147:42–52.PubMedGoogle Scholar
  118. 118.
    Sanvito F, Nichols A, Herrera P, Huarte J, Wohlwend A, Vassalli J, Orci L: TGF-B1 overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophy Res Comm 1995;217:1279–1286.CrossRefGoogle Scholar
  119. 119.
    Nagashio Y, Ueno H, Imamura M, Asaumi H, Watanabe S, Yamaguchi T, Taguchi M, Tashiro M, Otsuki M: Inhibition of transforming growth factor B decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice. Lab Invest 2004;84:1610–1618.PubMedCrossRefGoogle Scholar
  120. 120.
    Shek FW, Benyon RC, Walker FM, McCrudden PR, Pender SL, Williams EJ, Johnson PA, Johnson CD, Bateman AC, Fine DR, et al.: Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol 2002;160:1787–1798.PubMedGoogle Scholar
  121. 121.
    Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL: TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848–851.PubMedCrossRefGoogle Scholar
  122. 122.
    Bierie B, Moses HL: Tumour microenvironment: TGF[beta]: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006;6:506–520.PubMedCrossRefGoogle Scholar
  123. 123.
    Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO: Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci USA 2002;99:12877–12882.PubMedCrossRefGoogle Scholar
  124. 124.
    Hwang R, Yokoi K, Bucana C, Tsan R, Killion JJ, Evans DB, Fidler IJ: Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. Clin Cancer Res 2003;9:6534–6544.PubMedGoogle Scholar
  125. 125.
    Schneider E, Schmid-Kotsas A, Zhao J, Weidenbach H, Schmid RM, Menke A, Adler G, Waltenberger J, Grunert A, Bachem MG: 2001. Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. C532–C543.Google Scholar
  126. 126.
    Masamune A, Satoh M, Kikuta K, Suzuki N, Shimosegawa T: Activation of JAK-STAT pathway is required for platelet-derived growth factor-induced proliferation of pancratic stellate cells. World J Gastroenterol 2005;11:3385–3391.PubMedGoogle Scholar
  127. 127.
    Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, Parker NR, Toi CS, Pirola RC, Wilson JS, Goldstein D, et al.: Pancreatic Stellate Cells: Partners in Crime with Pancreatic Cancer Cells. Cancer Res 2008;68:2085–2093.PubMedCrossRefGoogle Scholar
  128. 128.
    Masamune A, Kikuta K, Satoh M, Suzuki N, Shimosegawa T: Green tea polyphenol epigallocatechin-3-gallate blocks PDGF-induced proliferation and migration of rat pancreatic stellate cells. World J Gastroenterol 2005;11:3368–3374.PubMedGoogle Scholar
  129. 129.
    Armstrong T, Packham G, Murphy LB, Bateman AC, Conti JA, Fine DR, Johnson CD, Benyon RC, Iredale JP: Type I Collagen Promotes the Malignant Phenotype of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2004;7427–7437.Google Scholar
  130. 130.
    Hartel M, Di Mola F, Gardini A, Zimmerman A, di Sebastiano P, Guweidhi A, Innocenti P, Giese T, Giese NA, Buchler MW, et al.: Desmoplastic reaction influences pancreatic cancer growth behavior. World J Surg 2004;28:818–825.PubMedCrossRefGoogle Scholar
  131. 131.
    Gao R, Birgstock D: Connective tissue growth factor (CCN2) in rat pancreatic stellate cell function: integrin alpha5 beta1 as a novel CCN2 receptor. Gastroenterology 2005;129:1019–1030.PubMedCrossRefGoogle Scholar
  132. 132.
    Aikawa T, Gunn J, Spong SM, Klaus SJ, Korc M: Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer. Mol Cancer Ther 2006;5:1108–1116.PubMedCrossRefGoogle Scholar
  133. 133.
    Dornhofer N, Spong S, Bennewith K, Salim A, Klaus S, Kambham N, Wong C, Kaper F, Sutphin P, Nacamuli R, et al.: Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 2006;66:5816–5827.PubMedCrossRefGoogle Scholar
  134. 134.
    Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su G, Hruban RH, Goggins M: SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene 2003;22:5021–5030.PubMedCrossRefGoogle Scholar
  135. 135.
    Muerkoster S, Wegenhenkel K, Arlt A, Witt M, Sipos B, Kruse M-L, Sebens T, Kloppel G, Kalthoff H, Folsch U, et al.: Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine efects of nitric oxide and interleukin-1B. Cancer Res 2004;15:1331–1337.CrossRefGoogle Scholar
  136. 136.
    Vaquero EC, Edderkaoui M, Nam KJ, Gukovsky I, Pandol SJ, Gukovskaya AS: Extracellular matrix proteins protect pancreatic cancer cells from death via mitochondrial and nonmitochondrial pathways. Gastroenterology 2003;125:1188–1202.PubMedCrossRefGoogle Scholar
  137. 137.
    Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S: Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 2004;28:38–44.PubMedCrossRefGoogle Scholar
  138. 138.
    Koninger J, Giese NA, di Mola F, Berberat P, Giese T, Esposito I, Bachem M, Buchler MW, Friess H: Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attneuation of chemotherapeutic action. Clin Cancer Res 2004;10:4776–4783.PubMedCrossRefGoogle Scholar
  139. 139.
    Muerkoster SS, Werbing V, Koch D, Sipos B, Ammerpohl O, Kalthoff H, Tsao MS, Folsch UR, Schafer H: Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma – epigenetic downregulation of caspases. Int J Cancer 2008;123:1751–1760.PubMedCrossRefGoogle Scholar
  140. 140.
    Ohuchida K, Mizumoto K, Murakami M, Qian L, Sato N, Nagai E, Matsumoto K, Nakamura T, Tanaka M: Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res 2004;64:3215–3222.PubMedCrossRefGoogle Scholar
  141. 141.
    Jura N, Archer H, Bar-Sagi D: Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between. Cell Res 2005;15:72–77.PubMedCrossRefGoogle Scholar
  142. 142.
    Garcea G, Dennison AR, Steward WP, Berry DP: Role of inflammation in pancreatic carcinogenesis and the implications for future therapy. Pancreatology 2005;5:514–529.PubMedCrossRefGoogle Scholar
  143. 143.
    Farrow B, Evers BM: Inflammation and the development of pancreatic cancer. Surg Oncol 2002;10:153–169.PubMedCrossRefGoogle Scholar
  144. 144.
    Algul H, Treiber M, Lesina M, Schmid RM: Mechanisms of disease: chronic inflammation and cancer in the pancreas – a potential role for pancreatic stellate cells? Nat Clin Pract Gastroenterol Hepatol 2007;4:454–462.PubMedCrossRefGoogle Scholar
  145. 145.
    Pelicano H, Carney D, Huang P: ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 2004;7:97–110.PubMedCrossRefGoogle Scholar
  146. 146.
    Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005;5:749–759.PubMedCrossRefGoogle Scholar
  147. 147.
    Schlosser W, Schlosser S, Ramadani M, Gansauge F, Gansauge S, Beger HG: Cyclooxygenase-2 is overexpressed in chronic pancreatitis. Pancreas 2002;25:26–30.PubMedCrossRefGoogle Scholar
  148. 148.
    Rakonczay Z, Jr., Hegyi P, Takacs T, McCarroll J, Saluja AK: The role of NF-kappaB activation in the pathogenesis of acute pancreatitis. Gut 2008;57:259–267.PubMedCrossRefGoogle Scholar
  149. 149.
    Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature 2008;454:436–444.PubMedCrossRefGoogle Scholar
  150. 150.
    Itzkowitz SH, Yio X: Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 2004;287:G7–G17.PubMedCrossRefGoogle Scholar
  151. 151.
    Farinati F, Cardin R, Cassaro M, Bortolami M, Nitti D, Tieppo C, Zaninotto G, Rugge M: Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway. Eur J Cancer Prev 2008;17:195–200.PubMedCrossRefGoogle Scholar
  152. 152.
    Pondugula K, Wani S, Sharma P: Barrett's esophagus and esophageal adenocarcinoma in adults: long-term GERD or something else? Curr Gastroenterol Rep 2007;9:468–474.PubMedCrossRefGoogle Scholar
  153. 153.
    Baumann B, Weber CK, Troppmair J, Whiteside S, Israel A, Rapp UR, Wirth T: Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proc Natl Acad Sci USA 2000;97:4615–4620.PubMedCrossRefGoogle Scholar
  154. 154.
    Repasky GA, Zhou Y, Morita S, Der CJ: Ras-mediated intestinal epithelial cell transformation requires cyclooxygenase-2-induced prostaglandin E2 signaling. Mol Carcinog 2007;46:958–970.PubMedCrossRefGoogle Scholar
  155. 155.
    Maciag A, Sithanandam G, Anderson LM: Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Carcinogenesis 2004;25:2231–2237.PubMedCrossRefGoogle Scholar
  156. 156.
    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.PubMedGoogle Scholar
  157. 157.
    Merati K, said Siadaty M, Andea A, Sarkar F, Ben-Josef E, Mohammad R, Philip P, Shields AF, Vaitkevicius V, Grignon DJ, et al.: Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters. Am J Clin Oncol 2001;24:447–452.PubMedCrossRefGoogle Scholar
  158. 158.
    Nagasaka T, Koi M, Kloor M, Gebert J, Vilkin A, Nishida N, Shin SK, Sasamoto H, Tanaka N, Matsubara N, et al.: Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology 2008;134:1950–1960, 1960 e1951.PubMedCrossRefGoogle Scholar
  159. 159.
    Brentnall TA, Chen R, Lee JG, Kimmey MB, Bronner MP, Haggitt RC, Kowdley KV, Hecker LM, Byrd DR: Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis. Cancer Res 1995;55:4264–4267.PubMedGoogle Scholar
  160. 160.
    Patti MG, Pellegrini CA: Gallstone pancreatitis. Surg Clin North Am 1990;70:1277–1295.PubMedGoogle Scholar
  161. 161.
    Saluja A, Saluja M, Villa A, Leli U, Rutledge P, Meldolesi J, Steer M: Pancreatic duct obstruction in rabbits causes digestive zymogen and lysosomal enzyme colocalization. J Clin Invest 1989;84:1260–1266.PubMedCrossRefGoogle Scholar
  162. 162.
    Lerch MM, Saluja AK, Runzi M, Dawra R, Saluja M, Steer ML: Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum. Gastroenterology 1993;104:853–861.PubMedGoogle Scholar
  163. 163.
    Esposito I, Seiler C, Bergmann F, Kleeff J, Friess H, Schirmacher P: Hypothetical progression model of pancreatic cancer with origin in the centroacinar-acinar compartment. Pancreas 2007;35:212–217.PubMedCrossRefGoogle Scholar
  164. 164.
    Wolff R, Varadhachary G, Evans D: Adjuvant therapy for adenocarcinooma of the pancreas: analysis of reported trials and recommendations for future progress. Ann Surg Onc 2008;15:2773–2786.CrossRefGoogle Scholar
  165. 165.
    Kojima K, Vickers SM, Adsay NV, Jhala NC, Kim HG, Schoeb TR, Grizzle WE, Klug CA: Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res 2007;67:8121–8130.PubMedCrossRefGoogle Scholar
  166. 166.
    Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, 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.PubMedCrossRefGoogle Scholar
  167. 167.
    Yang Y, Dukhanina O, Tang B, Mamura M, Letterio J, MacGregor J, Patel S, Khozin S, Liu Z, Green J, et al.: Lifetime exposure to a soluble TGF-B antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002;109:1607–1615.PubMedGoogle Scholar
  168. 168.
    Arteaga C: Inhibition of TGF[beta] signaling in cancer therapy. Curr Opin Genet Dev 2006;16:30–37.PubMedCrossRefGoogle Scholar
  169. 169.
    Wang XM, Ming D, Yu T, McCaughan GW, Gorrell MD: Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line. Hepatology 2005;42:935–945.PubMedCrossRefGoogle Scholar
  170. 170.
    Scott AM, Wiseman G, Welt S, Adjei A, Lee F-T, Hopkins W, Divgi CR, Hanson LH, Mitchell P, Gansen DN, et al.: A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer. Clin Cancer Res 2003;9:1639–1647.PubMedGoogle Scholar
  171. 171.
    Loeffler M, Kruger J, Niethammer A, Reisfeld R: Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 2006;116:1955–1962.PubMedCrossRefGoogle Scholar
  172. 172.
    Bramhall S, Schulz J, Nemunaitis J, Brown P, Baillet M, Buckels J: A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002;87:161–167.PubMedCrossRefGoogle Scholar
  173. 173.
    Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JAC: Marimastat as First-Line Therapy for Patients With Unresectable Pancreatic Cancer: A Randomized Trial. J Clin Oncol 2001;19:3447–3455.PubMedGoogle Scholar
  174. 174.
    Evans J, Stark A, Johnson C, Daniel F, Carmichael J, Buckels J, Imrie C, Brown P, Neoptolemos J: A phase II trial of marimastat in advanced pancreatic cancer. Br J Cancer 2001;85:1865–1870.PubMedCrossRefGoogle Scholar
  175. 175.
    Müerköster SS, Werbing V, Koch D, Sipos B, Ammerpohl O, Kalthoff H, Tsao M-S, Fölsch UR, Schäfer H: Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma - Epigenetic downregulation of caspases. Int J Cancer 2008;123:1751–1760.PubMedCrossRefGoogle Scholar
  176. 176.
    Marrache F, Pendyala S, Bhagat G, Betz KS, Song Z, Wang TC: Role of bone marrow-derived cells in experimental chronic pancreatitis. Gut 2008;57:1113–1120.PubMedCrossRefGoogle Scholar
  177. 177.
    Wrzesinski SH, Wan YY, Flavell RA: Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 2007;13:5262–5270.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Craig D. Logsdon
    • 1
  • Baoan Ji
    • 1
  • Rosa F. Hwang
    • 1
  1. 1.University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations