Skip to main content
SpringerLink
Log in

Molecular Targeted Therapies in Pancreatic Cancer

  • Chapter
  • First Online:
Molecular Genetics of Pancreatic Cancer

  • 1103 Accesses

Abstract

Pancreatic cancer, one of the deadliest malignancies, is a complex disease consisting of heterogeneous cancer cells with deregulated signaling pathways and a myriad of microenvironment cells, including infiltrating immune cells and fibroblasts, that impact tumor growth and susceptibility to conventional chemotherapy. Understanding the signaling pathways that drive pancreatic cancer is crucial to the development of novel targeted therapies to combat the disease, which is largely refractory to conventional therapeutic options. Among these pathways are the Hedgehog, NOTCH, Wnt, MET, and TGF-β pathways that control not only bulk tumor growth, but also self-renewal of cancer stem cells and maintenance of the desmoplastic stroma characteristic of the disease. In addition to altered signaling pathways, many cells within the tumor microenvironment promote both tumor growth and serve as a barrier to chemotherapy. Here we will discuss how targeting these components of the disease may increase the efficacy with which it is treated.

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 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
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

  • Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT, Hruban RH (2002) Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol 160(4):1361–1369

    PubMed  CAS  Google Scholar 

  • Amemiya H, Kono K, Itakura J, Tang RF, Takahashi A, An FQ, Kamei S, Iizuka H, Fujii H, Matsumoto Y (2002) c-Met expression in gastric cancer with liver metastasis. Oncology 63(3):286–296. doi: ocl63286 [pii]

    PubMed  CAS  Google Scholar 

  • Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H (1999) Notch signalling controls pancreatic cell differentiation. Nature 400(6747):877–881

    PubMed  CAS  Google Scholar 

  • Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, Ramm GA, Buchler M, Friess H, McCarroll JA, Keogh G, Merrett N, Pirola R, Wilson JS (2004) Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29(3):179–187

    PubMed  CAS  Google Scholar 

  • Arnold NB, Ketterer K, Kleeff J, Friess H, Buchler MW, Korc M (2004) Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer. Cancer Res 64(10):3599–3606. doi: 10.1158/0008-5472.CAN-03-2999 64/10/3599 [pii]

    PubMed  CAS  Google Scholar 

  • Artavanis-Tsakonas S, Matsuno K, Fortini ME (1995) Notch signaling. Science 268(5208):225–232

    PubMed  CAS  Google Scholar 

  • Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA (2008) Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res 14(19):5995–6004. doi: 14/19/5995 [pii] 10.1158/1078-0432.CCR-08-0291

    PubMed  CAS  Google Scholar 

  • Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA (2006) Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 20(22):3130–3146. doi: 20/22/3130 [pii] 10.1101/gad.1478706

    PubMed  CAS  Google Scholar 

  • Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH (2012) Tumor-­derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21(6):822–835. doi: 10.1016/j.ccr.2012.04.025

    PubMed  CAS  Google Scholar 

  • Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425(6960):846–851. doi: 10.1038/nature01972 nature01972 [pii]

    PubMed  CAS  Google Scholar 

  • Bettenhausen B, Hrabe de Angelis M, Simon D, Guenet JL, Gossler A (1995) Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development 121(8):2407–2418

    PubMed  CAS  Google Scholar 

  • Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH (1997) Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 74(3):301–309. doi:10.1002/(SICI)1097-0215(19970620)74:3<301::AID-IJC12>3.0.CO;2-E [pii]

    PubMed  CAS  Google Scholar 

  • Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, Arteaga CL, Moses HL (2001) Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 12(1):27–36

    PubMed  CAS  Google Scholar 

  • Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432(7015):332–337. doi: nature03096 [pii] 10.1038/nature03096

    PubMed  CAS  Google Scholar 

  • Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S (1997) Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell 90(2):281–291. doi: S0092-­8674(00)80336-0 [pii]

    PubMed  CAS  Google Scholar 

  • Boccaccio C, Comoglio PM (2006) Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 6(8):637–645. doi: nrc1912 [pii] 10.1038/nrc1912

    PubMed  CAS  Google Scholar 

  • Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737

    PubMed  CAS  Google Scholar 

  • Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal SA, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Griffin CA, Burton J, Swerdlow H, Quail MA, Stratton MR, Iacobuzio-Donahue C, Futreal PA (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113. doi: nature09460 [pii] ­10.1038/nature09460

    PubMed  CAS  Google Scholar 

  • Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67(19):9518–9527. doi: 67/19/9518 [pii] 10.1158/0008-5472.CAN-07-0175

    PubMed  CAS  Google Scholar 

  • Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480. doi: S0092-8674(06)01344-4 [pii] 10.1016/j.cell.2006.10.018

    PubMed  CAS  Google Scholar 

  • Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS, Ko AH, Olshen AB, Danenberg KL, Tempero MA, Spellman PT, Hanahan D, Gray JW (2011) Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 17(4):500–503. doi: nm.2344 [pii] 10.1038/nm.2344

    PubMed  CAS  Google Scholar 

  • Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-­Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. doi: doi:10.1056/NEJMoa1011923

    PubMed  CAS  Google Scholar 

  • Cook N, Frese KK, Bapiro TE, Jacobetz MA, Gopinathan A, Miller JL, Rao SS, Demuth T, Howat WJ, Jodrell DI, Tuveson DA (2012) Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med 209(3):437–444. doi: jem.20111923 [pii] 10.1084/jem.20111923

    PubMed  CAS  Google Scholar 

  • Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311(5981):29–33

    PubMed  CAS  Google Scholar 

  • Corso S, Migliore C, Ghiso E, De Rosa G, Comoglio PM, Giordano S (2008) Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene 27(5):684–693. doi: 1210697 [pii] 10.1038/sj.onc.1210697

    PubMed  CAS  Google Scholar 

  • D’Souza B, Miyamoto A, Weinmaster G (2008) The many facets of Notch ligands. Oncogene 27(38):5148–5167. doi: onc2008229 [pii] 10.1038/onc.2008.229

    PubMed  Google Scholar 

  • De La O JP, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB, Murtaugh LC (2008) Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A 105(48):18907–18912. doi: 0810111105 [pii] 10.1073/pnas.0810111105

    PubMed  Google Scholar 

  • DeNardo DG, Andreu P, Coussens LM (2010) Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev 29(2):309–316. doi: 10.1007/s10555-010-9223-6

    PubMed  Google Scholar 

  • Deonarain MP, Kousparou CA, Epenetos AA (2009) Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs 1(1):12–25

    PubMed  Google Scholar 

  • Dessimoz J, Bonnard C, Huelsken J, Grapin-Botton A (2005) Pancreas-specific deletion of beta-­catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr Biol 15(18):1677–1683. doi: 10.1016/j.cub.2005.08.037

    PubMed  CAS  Google Scholar 

  • Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S et al (1995a) Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1(2):147–154

    PubMed  Google Scholar 

  • Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR (1995b) Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res 55(5):1129–1138

    PubMed  Google Scholar 

  • Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Alison MR, Wright NA (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64(23):8492–8495. doi: 10.1158/0008-5472.can-04-1708

    PubMed  CAS  Google Scholar 

  • Dunwoodie SL, Henrique D, Harrison SM, Beddington RS (1997) Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124(16):3065–3076

    PubMed  CAS  Google Scholar 

  • Edlund S, Landström M, Heldin CH, Aspenström P (2002) Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA. Mol Biol Cell 13(3):902–914. doi: 10.1091/mbc.01-08-0398

    PubMed  CAS  Google Scholar 

  • Ellenrieder V, Buck A, Harth A, Jungert K, Buchholz M, Adler G, Urrutia R, Gress TM (2004) KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. Gastroenterology 127(2):607–620. doi: S0016508504008649 [pii]

    PubMed  CAS  Google Scholar 

  • Fiuza UM, Arias AM (2007) Cell and molecular biology of Notch. J Endocrinol 194(3):459–474. doi: 194/3/459 [pii] 10.1677/JOE-07-0242

    PubMed  CAS  Google Scholar 

  • Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P (2010) The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 10(8):554–567. doi: nri2808 [pii] 10.1038/nri2808

    PubMed  CAS  Google Scholar 

  • Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA (2002) Mastermind mediates chromatin-­specific transcription and turnover of the Notch enhancer complex. Genes Dev 16(11):1397–1411. doi: 10.1101/gad.991602

    PubMed  CAS  Google Scholar 

  • Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16(4):509–520. doi: S1097276504006409 [pii] 10.1016/j.molcel.2004.10.014

    PubMed  CAS  Google Scholar 

  • Gallahan D, Callahan R (1997) The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene 14(16):1883–1890. doi: 10.1038/sj.onc.1201035

    PubMed  CAS  Google Scholar 

  • Gallahan D, Jhappan C, Robinson G, Hennighausen L, Sharp R, Kordon E, Callahan R, Merlino G, Smith GH (1996) Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis. Cancer Res 56(8):1775–1785

    PubMed  CAS  Google Scholar 

  • Gao Z, Wang X, Wu K, Zhao Y, Hu G (2010) Pancreatic stellate cells increase the invasion of human pancreatic cancer cells through the stromal cell-derived factor-1/CXCR4 axis. Pancreatology 10(2–3):186–193. doi: 10.1159/000236012

    PubMed  Google Scholar 

  • Ghoussoub RA, Dillon DA, D’Aquila T, Rimm EB, Fearon ER, Rimm DL (1998) Expression of c-met is a strong independent prognostic factor in breast carcinoma. Cancer 82(8):1513–1520. doi:10.1002/(SICI)1097-0142(19980415)82:8<1513::AID-CNCR13>3.0.CO;2-7 [pii]

    PubMed  CAS  Google Scholar 

  • Gridley T (1997) Notch signaling in vertebrate development and disease. Mol Cell Neurosci 9(2):103–108. doi: S1044-7431(97)90610-2 [pii] 10.1006/mcne.1997.0610

    PubMed  CAS  Google Scholar 

  • Gridley T (2003) Notch signaling and inherited disease syndromes. Hum Mol Genet 12 Spec No. 1:R9–R13

    Google Scholar 

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66(3):589–600

    PubMed  CAS  Google Scholar 

  • Gupta S, Takebe N, Lorusso P (2010) Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol 2(4):237–250. doi: 10.1177/1758834010366430 10.1177_1758834010366430 [pii]

    PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi: S0092-8674(11)00127-9 [pii] 10.1016/j.cell.2011.02.013

    PubMed  CAS  Google Scholar 

  • Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47. doi: http://www.nature.com/nrc/journal/v2/n1/suppinfo/nrc704_S1.html

    Google Scholar 

  • Hartsough MT, Mulder KM (1995) Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem 270(13):7117–7124. doi: 10.1074/jbc.270.13.7117

    PubMed  CAS  Google Scholar 

  • Heller RS, Dichmann DS, Jensen J, Miller C, Wong G, Madsen OD, Serup P (2002) Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation. Dev Dyn 225(3):260–270. doi: 10.1002/dvdy.10157

    PubMed  CAS  Google Scholar 

  • Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323. doi: S1934-5909(07)00066-5 [pii] 10.1016/j.stem.2007.06.002

    PubMed  CAS  Google Scholar 

  • Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA (2006) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 20(10):1218–1249. doi: 20/10/1218 [pii] 10.1101/gad.1415606

    PubMed  CAS  Google Scholar 

  • Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4(6):437–450. doi: S153561080300309X [pii]

    PubMed  CAS  Google Scholar 

  • Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7(5):469–483. doi: S1535-6108(05)00128-5 [pii] 10.1016/j.ccr.2005.04.023

    PubMed  CAS  Google Scholar 

  • Hsieh JJ, Zhou S, Chen L, Young DB, Hayward SD (1999) CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci USA 96(1):23–28

    PubMed  CAS  Google Scholar 

  • Hua Z, Zhang YC, Hu XM, Jia ZG (2003) Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol 9(12):2764–2767

    PubMed  CAS  Google Scholar 

  • Humphrey PA, Zhu X, Zarnegar R, Swanson PE, Ratliff TL, Vollmer RT, Day ML (1995) Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147(2):386–396

    PubMed  CAS  Google Scholar 

  • Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68(3):918–926. doi: 68/3/918 [pii] 10.1158/0008-5472.CAN-07-5714

    PubMed  CAS  Google Scholar 

  • Ikenaga N, Ohuchida K, Mizumoto K, Cui L, Kayashima T, Morimatsu K, Moriyama T, Nakata K, Fujita H, Tanaka M (2010) CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer. Gastroenterology 139(3):1041–1051. doi: S0016-5085(10)00849-8 [pii] 10.1053/j.gastro.2010.05.084, 1051.e1–8

    PubMed  CAS  Google Scholar 

  • Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087. doi: 10.1101/gad.938601

    PubMed  CAS  Google Scholar 

  • Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, Deng CX, Hruban RH, Adsay NV, Tuveson DA, Hingorani SR (2007) Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11(3):229–243. doi: S1535-6108(07)00057-8 [pii] 10.1016/j.ccr.2007.01.017

    PubMed  CAS  Google Scholar 

  • Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP, Jiang P, Kultti A, Thompson CB, Maneval DC, Jodrell DI, Frost GI, Shepard HM, Skepper JN, Tuveson DA (2013) Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62(1):112–120. doi: 10.1136/gutjnl-2012-302529

    PubMed  CAS  Google Scholar 

  • Jaffee EM, Hruban RH, Canto M, Kern SE (2002) Focus on pancreas cancer. Cancer Cell 2(1):25–28. doi: 10.1016/s1535-6108(02)00093-4

    PubMed  CAS  Google Scholar 

  • Jensen J, Heller RS, Funder-Nielsen T, Pedersen EE, Lindsell C, Weinmaster G, Madsen OD, Serup P (2000) Independent development of pancreatic alpha- and beta-cells from neurogenin3-­expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes 49(2):163–176

    PubMed  CAS  Google Scholar 

  • Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, Callahan R (1992) Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev 6(3):345–355

    PubMed  CAS  Google Scholar 

  • Jimeno A, Feldmann G, Suárez-Gauthier A, Rasheed Z, Solomon A, Zou GM, Rubio-Viqueira B, García-García E, López-Ríos F, Matsui W, Maitra A, Hidalgo M (2009) A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther 8(2):310–314

    PubMed  CAS  Google Scholar 

  • Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321(5897):1801–1806. doi: 10.1126/science.1164368

    PubMed  CAS  Google Scholar 

  • Kalluri R (2009) EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 119(6):1417–1419. doi: 10.1172/jci39675

    PubMed  CAS  Google Scholar 

  • Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T (1998) A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev 12(15):2269–2277

    PubMed  CAS  Google Scholar 

  • Kelly RJ, Morris JC (2010) Transforming growth factor-beta: a target for cancer therapy. J Immunotoxicol 7(1):15–26. doi: 10.3109/15476910903389920

    PubMed  CAS  Google Scholar 

  • Kim EJ, Simeone DM (2011) Advances in pancreatic cancer. Curr Opin Gastroenterol 27(5):460–466. doi: 10.1097/MOG.0b013e328349e31f

    PubMed  Google Scholar 

  • Kobayashi T, Honke K, Gasa S, Miyazaki T, Tajima H, Matsumoto K, Nakamura T, Makita A (1994) Hepatocyte growth factor elevates the activity levels of glycolipid sulfotransferases in renal cell carcinoma cells. Eur J Biochem 219(1–2):407–413

    PubMed  CAS  Google Scholar 

  • Kohn AD, Moon RT (2005) Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 38(3–4):439–446. doi: 10.1016/j.ceca.2005.06.022

    PubMed  CAS  Google Scholar 

  • Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N, Imamura M (2000) Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res 6(9):3530–3535

    PubMed  CAS  Google Scholar 

  • Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330(6005):827–830. doi: 330/6005/827 [pii] 10.1126/science.1195300

    PubMed  CAS  Google Scholar 

  • Krymskaya VP, Hoffman R, Eszterhas A, Ciocca V, Panettieri RA (1997) TGF-β1 modulates EGF-­stimulated phosphatidylinositol 3-kinase activity in human airway smooth muscle cells. Am J Physiol 273(6):L1220–L1227

    PubMed  CAS  Google Scholar 

  • Kurooka H, Honjo T (2000) Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. J Biol Chem 275(22):17211–17220. doi: 10.1074/jbc.M000909200 M000909200 [pii]

    PubMed  CAS  Google Scholar 

  • Lauth M, Bergstrom A, Shimokawa T, Tostar U, Jin Q, Fendrich V, Guerra C, Barbacid M, Toftgard R (2010) DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 17(6):718–725. doi: nsmb.1833 [pii] 10.1038/nsmb.1833

    PubMed  CAS  Google Scholar 

  • Lee WY, Chen HH, Chow NH, Su WC, Lin PW, Guo HR (2005) Prognostic significance of co-­expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res 11(6):2222–2228. doi: 11/6/2222 [pii] 10.1158/1078-0432.CCR-04-1761

    PubMed  CAS  Google Scholar 

  • Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037. doi: 67/3/1030 [pii] 10.1158/0008-5472.CAN-06-2030

    PubMed  CAS  Google Scholar 

  • Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, Pasca di Magliano M, Simeone DM (2011) c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 141(6):2218.e5–2227.e5. doi: S0016-5085(11)01157-7 [pii] 10.1053/j.gastro.2011.08.009

    Google Scholar 

  • Lindsell CE, Shawber CJ, Boulter J, Weinmaster G (1995) Jagged: a mammalian ligand that activates Notch1. Cell 80(6):909–917. doi: 0092-8674(95)90294-5 [pii]

    PubMed  CAS  Google Scholar 

  • Lonardo E, Hermann PC, Mueller MT, Huber S, Balic A, Miranda-Lorenzo I, Zagorac S, Alcala S, Rodriguez-Arabaolaza I, Ramirez JC, Torres-Ruíz R, Garcia E, Hidalgo M, Cebrián DÁ, Heuchel R, Löhr M, Berger F, Bartenstein P, Aicher A, Heeschen C (2011) Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 9(5):433–446

    PubMed  CAS  Google Scholar 

  • Lyon M, Deakin JA, Mizuno K, Nakamura T, Gallagher JT (1994) Interaction of hepatocyte growth factor with heparan sulfate. Elucidation of the major heparan sulfate structural determinants. J Biol Chem 269(15):11216–11223

    PubMed  CAS  Google Scholar 

  • Malkoski SP, Wang XJ (2012) Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett. doi: S0014-5793(12)00101-9 [pii] 10.1016/j.febslet.2012.01.054

    Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-­mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. doi: S0092-8674(08)00444-3 [pii] 10.1016/j.cell.2008.03.027

    PubMed  CAS  Google Scholar 

  • Maroun CR, Naujokas MA, Holgado-Madruga M, Wong AJ, Park M (2000) The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol Cell Biol 20(22):8513–8525

    PubMed  CAS  Google Scholar 

  • Maroun CR, Naujokas MA, Park M (2003) Membrane targeting of Grb2-associated binder-1 (Gab1) scaffolding protein through Src myristoylation sequence substitutes for Gab1 pleckstrin homology domain and switches an epidermal growth factor response to an invasive morphogenic program. Mol Biol Cell 14(4):1691–1708. doi: 10.1091/mbc.E02-06-0352

    PubMed  CAS  Google Scholar 

  • Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805(1):105–117. doi: S0304-419X(09)00074-2 [pii] 10.1016/j.bbcan.2009.11.002

    PubMed  CAS  Google Scholar 

  • Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791. doi: 10.1146/annurev.biochem.67.1.753

    PubMed  CAS  Google Scholar 

  • McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, Settleman J (2007) Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci USA 104(50):19936–19941. doi: 0707498104 [pii] 10.1073/pnas.0707498104

    PubMed  CAS  Google Scholar 

  • Migliore C, Giordano S (2008) Molecular cancer therapy: can our expectation be MET? Eur J Cancer 44(5):641–651. doi: S0959-8049(08)00067-1 [pii] 10.1016/j.ejca.2008.01.022

    PubMed  CAS  Google Scholar 

  • Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3(6):565–576. doi: S1535610803001405 [pii]

    PubMed  CAS  Google Scholar 

  • Morel V, Lecourtois M, Massiani O, Maier D, Preiss A, Schweisguth F (2001) Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila. Curr Biol 11(10):789–792. doi: S0960-9822(01)00224-X [pii]

    PubMed  CAS  Google Scholar 

  • Morris JP 4th, Cano DA, Sekine S, Wang SC, Hebrok M (2010) Beta-catenin blocks Kras-­dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J Clin Invest 120(2):508–520. doi: 10.1172/JCI40045 40045 [pii]

    PubMed  CAS  Google Scholar 

  • Mucsi I, Skorecki KL, Goldberg HJ (1996) Extracellular signal-regulated kinase and the small GTP-binding protein, Rac, contribute to the effects of transforming growth factor-beta1 on gene expression. J Biol Chem 271(28):16567–16572. doi: 10.1074/jbc.271.28.16567

    PubMed  CAS  Google Scholar 

  • Mullendore ME, Koorstra JB, Li YM, Offerhaus GJ, Fan X, Henderson CM, Matsui W, Eberhart CG, Maitra A, Feldmann G (2009) Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res 15(7):2291–2301. doi: 1078-0432.CCR-08-2004 [pii] 10.1158/1078-0432.CCR-08-2004

    PubMed  CAS  Google Scholar 

  • Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631. doi: nrc2444 [pii] 10.1038/nrc2444

    PubMed  CAS  Google Scholar 

  • Murtaugh LC, Law AC, Dor Y, Melton DA (2005) Beta-catenin is essential for pancreatic acinar but not islet development. Development 132(21):4663–4674. doi: 10.1242/dev.02063

    PubMed  CAS  Google Scholar 

  • Nawroth R, van Zante A, Cervantes S, McManus M, Hebrok M, Rosen SD (2007) Extracellular sulfatases, elements of the Wnt signaling pathway, positively regulate growth and tumorigenicity of human pancreatic cancer cells. PLoS One 2(4):e392. doi: 10.1371/journal.pone.0000392

    PubMed  Google Scholar 

  • Nishimura T, Honda H, Takeichi M (2012) Planar cell polarity links axes of spatial dynamics in neural-tube closure. Cell 149(5):1084–1097

    PubMed  CAS  Google Scholar 

  • Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253(5020):665–669

    PubMed  CAS  Google Scholar 

  • Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernandez-Zapico ME, Hanahan D (2009) GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 23(1):24–36. doi: 23/1/24 [pii] 10.1101/gad.1753809

    PubMed  CAS  Google Scholar 

  • Olaku V, Matzke A, Mitchell C, Hasenauer S, Sakkaravarthi A, Pace G, Ponta H, Orian-Rousseau V (2011) c-Met recruits ICAM-1 as a coreceptor to compensate for the loss of CD44 in Cd44 null mice. Mol Biol Cell 22(15):2777–2786. doi: mbc.E11-02-0134 [pii] 10.1091/mbc.E11-02-0134

    PubMed  CAS  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, DeNicola G, Feig C, Combs C, Winter SP, Ireland-­Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461. doi: 10.1126/science.1171362

    PubMed  CAS  Google Scholar 

  • Onozuka H, Tsuchihara K, Esumi H (2011) Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs. Cancer Sci 102(5):975–982. doi: 10.1111/j.1349-7006.2011.01880.x

    PubMed  CAS  Google Scholar 

  • Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16(23):3074–3086. doi: 10.1101/gad.242602

    PubMed  CAS  Google Scholar 

  • Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Lee SH, Yoo NJ, Jang JJ, Pack S, Zhuang Z, Schmidt L, Zbar B, Lee JY (1999) Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59(2):307–310

    PubMed  CAS  Google Scholar 

  • Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T, Segara D, Dawson AC, Kench JG, Henshall SM, Sutherland RL, Dlugosz A, Rustgi AK, Hebrok M (2007) Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One 2(11):e1155. doi: 10.1371/journal.pone.0001155

    PubMed  Google Scholar 

  • Pasche B (2001) Role of transforming growth factor beta in cancer. J Cell Physiol 186(2):153–168. doi:10.1002/1097-4652(200002)186:2<153::aid-jcp1016>3.0.co;2-j

    PubMed  CAS  Google Scholar 

  • Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3(4):347–361. doi: S1535610803000850 [pii]

    PubMed  Google Scholar 

  • Plentz R, Park JS, Rhim AD, Abravanel D, Hezel AF, Sharma SV, Gurumurthy S, Deshpande V, Kenific C, Settleman J, Majumder PK, Stanger BZ, Bardeesy N (2009) Inhibition of gamma-­secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 136(5):1741.e6–1749.e6. doi: S0016-5085(09)00014-6 [pii] 10.1053/j.gastro.2009.01.008

    Google Scholar 

  • Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429

    PubMed  CAS  Google Scholar 

  • Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21(6):836–847. doi: 10.1016/j.ccr.2012.04.024

    PubMed  CAS  Google Scholar 

  • Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. doi: S0092-8674(10)00287-4 [pii] 10.1016/j.cell.2010.03.014

    PubMed  CAS  Google Scholar 

  • Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3(10):756–767. doi: 10.1038/nrc1186

    PubMed  CAS  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111. doi: 10.1038/35102167 35102167 [pii]

    PubMed  CAS  Google Scholar 

  • Reynolds TC, Smith SD, Sklar J (1987) Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the beta T cell receptor gene in human lymphoblastic neoplasms. Cell 50(1):107–117. doi: 0092-8674(87)90667-2 [pii]

    PubMed  CAS  Google Scholar 

  • Rowland-Goldsmith MA, Maruyama H, Kusama T, Ralli S, Korc M (2001) Soluble type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin Cancer Res 7(9): 2931–2940

    PubMed  CAS  Google Scholar 

  • Rowland-Goldsmith MA, Maruyama H, Matsuda K, Idezawa T, Ralli M, Ralli S, Korc M (2002) Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-­associated genes and suppresses pancreatic cancer cell metastasis. Mol Cancer Ther 1(3): 161–167

    PubMed  CAS  Google Scholar 

  • Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5(12):1026–1033. doi: nrd2086 [pii] 10.1038/nrd2086

    PubMed  CAS  Google Scholar 

  • Ruffell B, DeNardo DG, Affara NI, Coussens LM (2010) Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 21(1):3–10. doi: S1359-­6101(09)00109-9 [pii] 10.1016/j.cytogfr.2009.11.002

    PubMed  CAS  Google Scholar 

  • Ruiz i Altaba A, Palma V, Dahmane N (2002a) Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 3(1):24–33. doi: 10.1038/nrn704 nrn704 [pii]

    PubMed  CAS  Google Scholar 

  • Ruiz i Altaba A, Sanchez P, Dahmane N (2002b) Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2(5):361–372. doi: 10.1038/nrc796

    PubMed  CAS  Google Scholar 

  • Samowitz WS, Powers MD, Spirio LN, Nollet F, van Roy F, Slattery ML (1999) Beta-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res 59(7):1442–1444

    PubMed  CAS  Google Scholar 

  • Scales SJ, de Sauvage FJ (2009) Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30(6):303–312. doi: S0165-6147(09)00069-8 [pii] 10.1016/j.tips.2009.03.007

    PubMed  CAS  Google Scholar 

  • Schlingensiepen KH, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, Kielmanowicz M, Schneider A (2011) Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci 102(6):1193–1200. doi: 10.1111/j.1349-7006.2011.01917.x

    PubMed  CAS  Google Scholar 

  • Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16(1):68–73. doi: 10.1038/ng0597-68

    PubMed  CAS  Google Scholar 

  • Shawber C, Boulter J, Lindsell CE, Weinmaster G (1996) Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev Biol 180(1):370–376. doi: S0012-1606(96)90310-3 [pii] 10.1006/dbio.1996.0310

    PubMed  CAS  Google Scholar 

  • Shutter JR, Scully S, Fan W, Richards WG, Kitajewski J, Deblandre GA, Kintner CR, Stark KL (2000) Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev 14(11): 1313–1318

    PubMed  CAS  Google Scholar 

  • Sierra JR, Tsao MS (2011) c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol 3(1 Suppl):S21–S35. doi: 10.1177/1758834011422557 10.1177_ 1758834011422557 [pii]

    PubMed  CAS  Google Scholar 

  • Singh S, Srivastava SK, Bhardwaj A, Owen LB, Singh AP (2010) CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer 103(11):1671–1679. doi: http://www.nature.com/bjc/journal/v103/n11/suppinfo/6605968s1.html

    Google Scholar 

  • Soman NR, Correa P, Ruiz BA, Wogan GN (1991) The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci U S A 88(11):4892–4896

    PubMed  CAS  Google Scholar 

  • Sonnenberg E, Meyer D, Weidner KM, Birchmeier C (1993) Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol 123(1):223–235

    PubMed  CAS  Google Scholar 

  • Suzuki K, Hayashi N, Yamada Y, Yoshihara H, Miyamoto Y, Ito Y, Ito T, Katayama K, Sasaki Y, Ito A et al (1994) Expression of the c-met protooncogene in human hepatocellular carcinoma. Hepatology 20(5):1231–1236. doi: S0270913994003459 [pii]

    PubMed  CAS  Google Scholar 

  • Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M, Kuo C, Wang HJ, Hoon DS (2003) c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9(4):1480–1488

    PubMed  CAS  Google Scholar 

  • Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, Adsay V, Abrams RA, Cameron JL, Kern SE, Yeo CJ, Hruban RH, Goggins M (2001) The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res 7(12):4115–4121

    PubMed  CAS  Google Scholar 

  • Terabe M, Ambrosino E, Takaku S, O’Konek JJ, Venzon D, Lonning S, McPherson JM, Berzofsky JA (2009) Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res 15(21):6560–6569. doi: 1078-0432.CCR-09-1066 [pii] 10.1158/1078-0432.CCR-09-1066

    PubMed  CAS  Google Scholar 

  • Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425(6960):851–856. doi: 10.1038/nature02009 nature02009 [pii]

    PubMed  CAS  Google Scholar 

  • Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11(12):834–848. doi: nrm3012 [pii] 10.1038/nrm3012

    PubMed  CAS  Google Scholar 

  • Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH (2006) Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 5(3):483–493. doi: 5/3/483 [pii] 10.1158/1535-7163.MCT-05-0299

    PubMed  CAS  Google Scholar 

  • Wang L, Heidt DG, Lee CJ, Yang H, Logsdon CD, Zhang L, Fearon ER, Ljungman M, Simeone DM (2009a) Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell 15(3):207–219. doi: 10.1016/j.ccr.2009.01.018

    PubMed  CAS  Google Scholar 

  • Wang P, Fan J, Chen Z, Meng ZQ, Luo JM, Lin JH, Zhou ZH, Chen H, Wang K, Xu ZD, Liu LM (2009b) Low-level expression of Smad7 correlates with lymph node metastasis and poor prognosis in patients with pancreatic cancer. Ann Surg Oncol 16(4):826–835. doi: 10.1245/s10434-008-0284-5

    PubMed  Google Scholar 

  • Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH (2009c) Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-­resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res 69(6):2400–2407. doi: 10.1158/0008-5472.can-08-4312

    PubMed  CAS  Google Scholar 

  • Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W (1996) Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384(6605):173–176. doi: 10.1038/384173a0

    PubMed  CAS  Google Scholar 

  • Wells JM, Esni F, Boivin GP, Aronow BJ, Stuart W, Combs C, Sklenka A, Leach SD, Lowy AM (2007) Wnt/beta-catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol 7:4. doi: 10.1186/1471-213X-7-4

    PubMed  Google Scholar 

  • Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60(7):2002–2006

    PubMed  CAS  Google Scholar 

  • Willert K, Jones KA (2006) Wnt signaling: is the party in the nucleus? Genes Dev 20(11):1394–1404. doi: 20/11/1394 [pii] 10.1101/gad.1424006

    PubMed  CAS  Google Scholar 

  • Yokoi K, Fidler IJ (2004) Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine. Clin Cancer Res 10(7):2299–2306. doi: 10.1158/1078-0432.ccr-03-0488

    PubMed  CAS  Google Scholar 

  • Zarnegar R, Michalopoulos GK (1995) The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129(5):1177–1180. doi: 10.1083/jcb.129.5.1177

    PubMed  CAS  Google Scholar 

  • Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD (2000) SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. Mol Cell Biol 20(7):2400–2410

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Edward Kim

  2. Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Ethan V. Abel, Arunima Ghosh & Diane M. Simeone M.D.

  3. Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Diane M. Simeone M.D.

Authors
  1. Edward Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ethan V. Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arunima Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diane M. Simeone M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Diane M. Simeone M.D. .

Editor information

Editors and Affiliations

  1. MED CTR ROOM 2922D, TC, University of Michigan, E Medical CTR Drive 1500, Ann Arbor, 48109-0999, Michigan, USA

    Diane M. Simeone

  2. CRB 2/STE 345, Johns Hopkins University, Orleans Street 1550, Baltimore, 21231, Maryland, USA

    Anirban Maitra

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Kim, E., Abel, E.V., Ghosh, A., Simeone, D.M. (2013). Molecular Targeted Therapies in Pancreatic Cancer. In: Simeone, D., Maitra, A. (eds) Molecular Genetics of Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6549-2_6

Download citation

Publish with us

Policies and ethics

Search

Navigation