Skip to main content
SpringerLink
Log in

Strategies to Target Pancreatic Cancer

  • Chapter
  • First Online:
Molecular Targets and Strategies in Cancer Prevention

  • 511 Accesses

Abstract

Pancreatic cancer has the highest mortality rate among all major types of solid cancers. Due to early metastasis to other organs, late detection and high resistance to chemotherapy, only 5–6 % of pancreatic cancer patients will survive more than 5 years after diagnosis. Critical issues for increasing patient survival are (1) to develop new methods for early detection of tumor development or cancer cell dissemination, and (2) to develop new treatment strategies that target chemoresistance and the desmoplastic reaction and make tumor cells accessible to conventional chemotherapy. In this chapter, we discuss genetic alterations that can lead to the development of pancreatic cancer, possibilities for early detection of pancreatic cancer, as well as strategies targeting signaling pathways involved in mediating resistance to chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2(12):897–909.

    Article  CAS  PubMed  Google Scholar 

  2. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371(11):1039–49.

    Article  CAS  PubMed  Google Scholar 

  3. Bardeesy N, et al. The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model. Semin Cancer Biol. 2001;11(3):201–18.

    Article  CAS  PubMed  Google Scholar 

  4. Hausmann S, et al. The role of inflammation in pancreatic cancer. Adv Exp Med Biol. 2014;816:129–51.

    Article  CAS  PubMed  Google Scholar 

  5. Ling S, et al. Inflammation to cancer: the molecular biology in the pancreas (review). Oncol Lett. 2014;7(6):1747–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Meier JJ, Giese A. Diabetes associated with pancreatic diseases. Curr Opin Gastroenterol. 2015;31(5):400–6.

    Article  CAS  PubMed  Google Scholar 

  7. Hahn SA, et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003;95(3):214–21.

    Article  CAS  PubMed  Google Scholar 

  8. Murphy KM, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17 %. Cancer Res. 2002;62(13):3789–93.

    CAS  PubMed  Google Scholar 

  9. Slater EP, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010;78(5):490–4.

    Article  CAS  PubMed  Google Scholar 

  10. Jones S, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Foulkes WD, et al. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 2007;9(6):R83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Rahman N, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165–7.

    Article  CAS  PubMed  Google Scholar 

  13. Tischkowitz M, et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A. 2007;104(16):6788–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bartsch DK, et al. CDKN2A germline mutations in familial pancreatic cancer. Ann Surg. 2002;236(6):730–7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Goldstein AM, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995;333(15):970–4.

    Article  CAS  PubMed  Google Scholar 

  16. Rizos H, et al. A melanoma-associated germline mutation in exon 1beta inactivates p14ARF. Oncogene. 2001;20(39):5543–7.

    Article  CAS  PubMed  Google Scholar 

  17. Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;333(15):975–7.

    Article  CAS  PubMed  Google Scholar 

  18. Karuman P, et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell. 2001;7(6):1307–19.

    Article  CAS  PubMed  Google Scholar 

  19. Marignani PA, Kanai F, Carpenter CL. LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. J Biol Chem. 2001;276(35):32415–8.

    Article  CAS  PubMed  Google Scholar 

  20. Tiainen M, et al. Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum Mol Genet. 2002;11(13):1497–504.

    Article  CAS  PubMed  Google Scholar 

  21. Su GH, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol. 1999;154(6):1835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Grant RC, et al. Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer. Hum Genomics. 2013;7:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Grant RC, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015;148(3):556–64.

    Article  CAS  PubMed  Google Scholar 

  24. Roberts NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2(1):41–6.

    Article  CAS  PubMed  Google Scholar 

  25. Geoffroy-Perez B, et al. Cancer risk in heterozygotes for ataxia-telangiectasia. Int J Cancer. 2001;93(2):288–93.

    Article  CAS  PubMed  Google Scholar 

  26. Swift M, et al. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med. 1987;316(21):1289–94.

    Article  CAS  PubMed  Google Scholar 

  27. Swift M, et al. Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res. 1976;36(1):209–15.

    CAS  PubMed  Google Scholar 

  28. Taylor AM, Byrd PJ. Molecular pathology of ataxia telangiectasia. J Clin Pathol. 2005;58(10):1009–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Harada T, et al. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene. 2008;27(13):1951–60.

    Article  CAS  PubMed  Google Scholar 

  30. Kimmelman AC, et al. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci U S A. 2008;105(49):19372–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Campbell PJ, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Janda E, et al. Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway. Oncogene. 2002;21(33):5148–59.

    Article  CAS  PubMed  Google Scholar 

  33. Sansom OJ, et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc Natl Acad Sci U S A. 2006;103(38):14122–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wislez M, et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res. 2005;65(8):3226–35.

    CAS  PubMed  Google Scholar 

  35. Grippo PJ, et al. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 2003;63(9):2016–9.

    CAS  PubMed  Google Scholar 

  36. Collins MA, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hingorani SR, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4(6):437–50.

    Article  CAS  PubMed  Google Scholar 

  38. Ardito CM, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012;22(3):304–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kopp JL, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22(6):737–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liou GY, et al. Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. Cancer Discov. 2015;5(1):52–63.

    Article  CAS  PubMed  Google Scholar 

  41. Means AL, et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development. 2005;132(16):3767–76.

    Article  CAS  PubMed  Google Scholar 

  42. Collisson EA, et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012;2(8):685–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liou GY, et al. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs. J Cell Biol. 2013;202(3):563–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Aguirre AJ, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 2003;17(24):3112–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bardeesy N, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20(22):3130–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hingorani SR, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7(5):469–83.

    Article  CAS  PubMed  Google Scholar 

  47. Izeradjene K, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell. 2007;11(3):229–43.

    Article  CAS  PubMed  Google Scholar 

  48. Kojima K, et al. Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia. Cancer Res. 2007;67(17):8121–30.

    Article  CAS  PubMed  Google Scholar 

  49. Morton JP, et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci U S A. 2010;107(1):246–51.

    Article  CAS  PubMed  Google Scholar 

  50. Baumgart S, et al. Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. Cancer Discov. 2014;4(6):688–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Guerra C, et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11(3):291–302.

    Article  CAS  PubMed  Google Scholar 

  52. Kruger B, Albrecht E, Lerch MM. The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis. Am J Pathol. 2000;157(1):43–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nagai H, et al. Role of pancreatic enzymes and their substrates in autodigestion of the pancreas. In vitro studies with isolated rat pancreatic acini. Gastroenterology. 1989;96(3):838–47.

    Article  CAS  PubMed  Google Scholar 

  54. Kereszturi E, et al. Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. Hum Mutat. 2009;30(4):575–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rustgi AK. Familial pancreatic cancer: genetic advances. Genes Dev. 2014;28(1):1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Whitcomb DC, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14(2):141–5.

    Article  CAS  PubMed  Google Scholar 

  57. Teich N, et al. Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Hum Mutat. 2006;27(8):721–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Weiss FU, et al. Local clustering of PRSS1 R122H mutations in hereditary pancreatitis patients from Northern Germany. Am J Gastroenterol. 2008;103(10):2585–8.

    Article  CAS  PubMed  Google Scholar 

  59. Archer H, et al. A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology. 2006;131(6):1844–55.

    Article  CAS  PubMed  Google Scholar 

  60. Witt H, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000;25(2):213–6.

    Article  CAS  PubMed  Google Scholar 

  61. Le Marechal C, et al. Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis. Hum Mutat. 2004;23(2):205.

    Article  PubMed  Google Scholar 

  62. Rosendahl J, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40(1):78–82.

    Article  CAS  PubMed  Google Scholar 

  63. Cohn JA, Bornstein JD, Jowell PS. Cystic fibrosis mutations and genetic predisposition to idiopathic chronic pancreatitis. Med Clin North Am. 2000;84(3):621–31. ix.

    Article  CAS  PubMed  Google Scholar 

  64. Cohn JA, et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339(10):653–8.

    Article  CAS  PubMed  Google Scholar 

  65. Kiraly O, Wartmann T, Sahin-Toth M. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut. 2007;56(10):1433–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Derikx MH, et al. Tropical calcific pancreatitis and its association with CTRC and SPINK1 (p.N34S) variants. Eur J Gastroenterol Hepatol. 2009;21(8):889–94.

    Article  PubMed  Google Scholar 

  67. Szmola R, Sahin-Toth M. Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells. Gut. 2010;59(3):365–72.

    Article  CAS  PubMed  Google Scholar 

  68. Ahmed N, et al. Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Gut. 2003;52(8):1159–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Choi JY, et al. Aberrant CFTR-dependent HCO3-transport in mutations associated with cystic fibrosis. Nature. 2001;410(6824):94–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ooi CY, et al. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology. 2011;140(1):153–61.

    Article  CAS  PubMed  Google Scholar 

  71. Soeth E, et al. Detection of tumor cell dissemination in pancreatic ductal carcinoma patients by CK 20 RT-PCR indicates poor survival. J Cancer Res Clin Oncol. 2005;131(10):669–76.

    Article  PubMed  Google Scholar 

  72. Tjensvoll K, Nordgard O, Smaaland R. Circulating tumor cells in pancreatic cancer patients: methods of detection and clinical implications. Int J Cancer. 2014;134(1):1–8.

    Article  PubMed  CAS  Google Scholar 

  73. Zhou J, et al. Marker expression in circulating cancer cells of pancreatic cancer patients. J Surg Res. 2011;171(2):631–6.

    Article  CAS  PubMed  Google Scholar 

  74. An Q, et al. Detection of p16 hypermethylation in circulating plasma DNA of non-small cell lung cancer patients. Cancer Lett. 2002;188(1–2):109–14.

    Article  CAS  PubMed  Google Scholar 

  75. Tada M, et al. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993;53(11):2472–4.

    CAS  PubMed  Google Scholar 

  76. Yamada T, et al. Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features. Clin Cancer Res. 1998;4(6):1527–32.

    CAS  PubMed  Google Scholar 

  77. Clarke LE, et al. Epidermal growth factor receptor mRNA in peripheral blood of patients with pancreatic, lung, and colon carcinomas detected by RT-PCR. Int J Oncol. 2003;22(2):425–30.

    CAS  PubMed  Google Scholar 

  78. Hoffmann K, et al. Detection of disseminated pancreatic cells by amplification of cytokeratin-19 with quantitative RT-PCR in blood, bone marrow and peritoneal lavage of pancreatic carcinoma patients. World J Gastroenterol. 2007;13(2):257–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rhim AD, et al. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology. 2014;146(3):647–51.

    Article  PubMed  Google Scholar 

  80. Z’Graggen K, et al. Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients. Surgery. 2001;129(5):537–46.

    Article  PubMed  Google Scholar 

  81. Rhim AD, et al. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148(1–2):349–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Alix-Panabieres C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu Rev Med. 2012;63:199–215.

    Article  CAS  PubMed  Google Scholar 

  83. Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer—a survey. Biochim Biophys Acta. 2007;1775(1):181–232.

    CAS  PubMed  Google Scholar 

  84. Bettegowda C, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Lecomte T, et al. Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int J Cancer. 2002;100(5):542–8.

    Article  CAS  PubMed  Google Scholar 

  86. Sozzi G, et al. Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res. 2001;61(12):4675–8.

    CAS  PubMed  Google Scholar 

  87. Dawson SJ, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–209.

    Article  CAS  PubMed  Google Scholar 

  88. Maheswaran S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Punnoose EA, et al. Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. Clin Cancer Res. 2012;18(8):2391–401.

    Article  CAS  PubMed  Google Scholar 

  90. Halkova T, et al. MicroRNAs in pancreatic cancer: involvement in carcinogenesis and potential use for diagnosis and prognosis. Gastroenterol Res Pract. 2015;2015:892903.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Ryu JK, et al. Aberrant MicroRNA-155 expression is an early event in the multistep progression of pancreatic adenocarcinoma. Pancreatology. 2010;10(1):66–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Habbe N, et al. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther. 2009;8(4):340–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee EJ, et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 2007;120(5):1046–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu J, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–8.

    Article  CAS  PubMed  Google Scholar 

  95. Roldo C, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–84.

    Article  CAS  PubMed  Google Scholar 

  96. Volinia S, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103(7):2257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Baffa R, et al. MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol. 2009;219(2):214–21.

    Article  CAS  PubMed  Google Scholar 

  98. Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med. 2009;60:167–79.

    Article  CAS  PubMed  Google Scholar 

  99. Gregory PA, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.

    Article  CAS  PubMed  Google Scholar 

  100. Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449(7163):682–8.

    Article  CAS  PubMed  Google Scholar 

  101. Wang Z, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8(1):27–33.

    Article  CAS  PubMed  Google Scholar 

  102. Berlin JD, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20(15):3270–5.

    Article  CAS  PubMed  Google Scholar 

  103. Heinemann V, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24(24):3946–52.

    Article  CAS  PubMed  Google Scholar 

  104. Herrmann R, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol. 2007;25(16):2212–7.

    Article  CAS  PubMed  Google Scholar 

  105. Cascinu S, et al. New target therapies in advanced pancreatic cancer. Ann Oncol. 2006;17 Suppl 5:v148–52.

    Article  PubMed  Google Scholar 

  106. Kindler HL, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005;23(31):8033–40.

    Article  CAS  PubMed  Google Scholar 

  107. Moore MJ, 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 Group. J Clin Oncol. 2007;25(15):1960–6.

    Article  CAS  PubMed  Google Scholar 

  108. Ciliberto D, et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer. 2013;49(3):593–603.

    Article  CAS  PubMed  Google Scholar 

  109. Arlt A, et al. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003;22(21):3243–51.

    Article  CAS  PubMed  Google Scholar 

  110. Hermann PC, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–23.

    Article  CAS  PubMed  Google Scholar 

  111. Hong SP, et al. CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Int J Cancer. 2009;125(10):2323–31.

    Article  CAS  PubMed  Google Scholar 

  112. Pan X, et al. Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008;14(24):8143–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shah AN, et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14(12):3629–37.

    Article  PubMed  Google Scholar 

  114. Wang Z, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69(6):2400–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Allen E, Walters IB, Hanahan D. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res. 2011;17(16):5299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Beatty GL, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Olive KP, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Cucinotto I, et al. Nanoparticle albumin bound Paclitaxel in the treatment of human cancer: nanodelivery reaches prime-time? J Drug Deliv. 2013;2013:905091.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Szakacs G, et al. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5(3):219–34.

    Article  CAS  PubMed  Google Scholar 

  120. Hagmann W, et al. ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology. 2009;9(1–2):136–44.

    Article  CAS  PubMed  Google Scholar 

  121. Konig J, et al. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int J Cancer. 2005;115(3):359–67.

    Article  PubMed  CAS  Google Scholar 

  122. Misra S, Ghatak S, Toole BP. Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2. J Biol Chem. 2005;280(21):20310–5.

    Article  CAS  PubMed  Google Scholar 

  123. Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 2001;42(7):1007–17.

    CAS  PubMed  Google Scholar 

  124. Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics. 2009;3(3):281–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chen M, et al. Expression and promoter methylation analysis of ATP-binding cassette genes in pancreatic cancer. Oncol Rep. 2012;27(1):265–9.

    CAS  PubMed  Google Scholar 

  126. Hagmann W, Jesnowski R, Lohr JM. Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia. 2010;12(9):740–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Oguri T, et al. The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity. Mol Cancer Ther. 2006;5(7):1800–6.

    Article  CAS  PubMed  Google Scholar 

  128. Tsujie M, et al. Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer. Anticancer Res. 2007;27(4B):2241–9.

    CAS  PubMed  Google Scholar 

  129. Poplin E, et al. Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol. 2013;31(35):4453–61.

    Article  CAS  PubMed  Google Scholar 

  130. Ripka S, et al. CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer. Gut. 2010;59(8):1101–10.

    Article  CAS  PubMed  Google Scholar 

  131. Bondar VM, et al. Inhibition of the phosphatidylinositol 3′-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. Mol Cancer Ther. 2002;1(12):989–97.

    CAS  PubMed  Google Scholar 

  132. Ng SS, et al. Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin Cancer Res. 2001;7(10):3269–75.

    CAS  PubMed  Google Scholar 

  133. Ng SSW, et al. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res. 2000;60(19):5451–5.

    CAS  PubMed  Google Scholar 

  134. Fahy BN, et al. Inhibition of AKT abrogates chemotherapy-induced NF-kappaB survival mechanisms: implications for therapy in pancreatic cancer. J Am Coll Surg. 2004;198(4):591–9.

    Article  PubMed  Google Scholar 

  135. Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001;107(3):241–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rogatsky I, Adelman K. Preparing the first responders: building the inflammatory transcriptome from the ground up. Mol Cell. 2014;54(2):245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Trauzold A, et al. CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene. 2001;20(31):4258–69.

    Article  CAS  PubMed  Google Scholar 

  138. Doppler H, Liou GY, Storz P. Downregulation of TRAF2 mediates NIK-induced pancreatic cancer cell proliferation and tumorigenicity. PLoS One. 2013;8(1):e53676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Banerjee S, et al. 3,3′-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res. 2009;69(13):5592–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol. 2002;64(5-6):883–8.

    Article  CAS  PubMed  Google Scholar 

  141. Schech AJ, et al. Zoledronic acid reverses the epithelial-mesenchymal transition and inhibits self-renewal of breast cancer cells through inactivation of NF-kappaB. Mol Cancer Ther. 2013;12(7):1356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Tassone P, et al. Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro. Br J Cancer. 2003;88(12):1971–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Bao B, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011;307(1):26–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Gungor C, et al. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res. 2011;71(14):5009–19.

    Article  PubMed  CAS  Google Scholar 

  145. Kang M, et al. Delta like ligand 4 induces impaired chemo-drug delivery and enhanced chemoresistance in pancreatic cancer. Cancer Lett. 2013;330(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  146. DeNicola GM, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475(7354):106–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lister A, et al. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer. 2011;10:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hong YB, et al. Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells. Pancreas. 2010;39(4):463–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Jimeno A, et al. A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther. 2009;8(2):310–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li Y, et al. Pancreatic cancer stem cells: emerging target for designing novel therapy. Cancer Lett. 2013;338(1):94–100.

    Article  CAS  PubMed  Google Scholar 

  151. Xia J, et al. Targeting pancreatic cancer stem cells for cancer therapy. Biochim Biophys Acta. 2012;1826(2):385–99.

    CAS  PubMed  Google Scholar 

  152. Huang FT, et al. Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int J Oncol. 2012;41(5):1707–14.

    CAS  PubMed  Google Scholar 

  153. Lonardo E, et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell. 2011;9(5):433–46.

    Article  CAS  PubMed  Google Scholar 

  154. Mueller MT, et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology. 2009;137(3):1102–13.

    Article  CAS  PubMed  Google Scholar 

  155. Palagani V, et al. Epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells are inhibited by gamma-secretase inhibitor IX. PLoS One. 2012;7(10):e46514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kapoor A, et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014;158(1):185–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hao Y, et al. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283(9):5496–509.

    Article  CAS  PubMed  Google Scholar 

  158. Oka T, Mazack V, Sudol M. Mst2 and Lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP). J Biol Chem. 2008;283(41):27534–46.

    Article  CAS  PubMed  Google Scholar 

  159. Zhang J, Smolen GA, Haber DA. Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. Cancer Res. 2008;68(8):2789–94.

    Article  CAS  PubMed  Google Scholar 

  160. Zhao B, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21(21):2747–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zhao B, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22(14):1962–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Serrano I, et al. Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat Commun. 2013;4:2976.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Sato N, et al. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene. 2003;22(32):5021–30.

    Article  CAS  PubMed  Google Scholar 

  164. Chlenski A, et al. SPARC enhances tumor stroma formation and prevents fibroblast activation. Oncogene. 2007;26(31):4513–22.

    Article  CAS  PubMed  Google Scholar 

  165. Miyoshi K, et al. SPARC mRNA expression as a prognostic marker for pancreatic adenocarcinoma patients. Anticancer Res. 2010;30(3):867–71.

    CAS  PubMed  Google Scholar 

  166. Sinn M, et al. SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study. Ann Oncol. 2014;25(5):1025–32.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work by the authors is supported by the NIH grant CA140182 (to P.S.), and a postdoctoral fellowship grant from the Center for Regenerative Medicine at Mayo Clinic (to G.-Y.L.).

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA

    Geou-Yarh Liou & Peter Storz

Authors
  1. Geou-Yarh Liou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Storz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Storz .

Editor information

Editors and Affiliations

  1. Pharmaceutical Technology, Jadavpur University, Kolkata, India

    Malay Chatterjee

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Liou, GY., Storz, P. (2016). Strategies to Target Pancreatic Cancer. In: Chatterjee, M. (eds) Molecular Targets and Strategies in Cancer Prevention. Springer, Cham. https://doi.org/10.1007/978-3-319-31254-5_1

Download citation

Publish with us

Policies and ethics

Search

Navigation