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Apoptosis: Signaling Pathways in Pancreatic Cancer Pathogenesis

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Pancreatic Cancer

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Abstract

Conventional and investigational cancer therapies have had little to no effect on the course of pancreatic cancer disease progression. Because apoptosis plays a major role in the effects of conventional chemo- and radiotherapy, it has been widely assumed that apoptotic pathways must be disrupted more frequently in pancreatic cancer than they are in other solid malignancies. However, comprehensive genomic characterizations of primary pancreatic cancers do not support this conclusion. Rather, it appears that one of the recently identified molecular subtypes of pancreatic cancer (quasimesenchymal/basal-like/squamous) that shares similarities with basal-like breast and bladder cancers contains tumors that are most likely to be apoptosis sensitive and responsive to conventional chemotherapy. Otherwise it is not immediately obvious how the molecular and genomic properties of pancreatic cancers would be expected to impart apoptosis resistance, providing indirect but strong support for the conclusions that late diagnosis and the extent to which tumor-stromal interactions reinforce apoptosis resistance represent the truly unique challenges to effective clinical control of the disease. This book chapter will provide an update of what has been learned recently about the molecular control of apoptosis in pancreatic cancer and how the information might be exploited in the design of more effective therapeutic regimens.

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References

  1. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57. PubMed PMID: 4561027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980;284(5756):555–6. PubMed PMID: 6245367.

    Article  CAS  PubMed  Google Scholar 

  3. Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986;44(6):817–29. PubMed PMID: 3955651.

    Article  CAS  PubMed  Google Scholar 

  4. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993;75(4):641–52. PubMed PMID: 8242740.

    Article  CAS  PubMed  Google Scholar 

  5. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6. PubMed PMID: 11048727.

    Article  CAS  PubMed  Google Scholar 

  6. Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89(2):175–84. PubMed PMID: 9108473.

    Article  CAS  PubMed  Google Scholar 

  7. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90(3):405–13. PubMed PMID: 9267021.

    Article  CAS  PubMed  Google Scholar 

  8. Zou H, Li Y, Liu X, Wang X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem. 1999;274(17):11549–56. PubMed PMID: 10206961.

    Article  CAS  PubMed  Google Scholar 

  9. Tsujimoto Y, Cossman J, Jaffe E, Croce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985;228(4706):1440–3. PubMed PMID: 3874430.

    Article  CAS  PubMed  Google Scholar 

  10. Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. 1985;41(3):899–906. PubMed PMID: 3924412.

    Article  CAS  PubMed  Google Scholar 

  11. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al. Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989;57(1):79–88. PubMed PMID: 2649247.

    Article  CAS  PubMed  Google Scholar 

  12. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, et al. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993;74(4):597–608. PubMed PMID: 8358789.

    Article  CAS  PubMed  Google Scholar 

  13. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348(6299):334–6. PubMed PMID: 2250705.

    Article  CAS  PubMed  Google Scholar 

  14. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4):609–19. PubMed PMID: 8358790.

    Article  CAS  PubMed  Google Scholar 

  15. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324–37. PubMed PMID: 17322918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Antignani A, Youle RJ. How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol. 2006;18(6):685–9. PubMed PMID: 17046225.

    Article  CAS  PubMed  Google Scholar 

  17. Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002;2(3):183–92. PubMed PMID: 12242151.

    Article  CAS  PubMed  Google Scholar 

  18. Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7(10):988–94. PubMed PMID: 17016456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol. 1999;11(2):255–60. PubMed PMID: 10209153.

    Article  CAS  PubMed  Google Scholar 

  20. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, et al. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature. 2009;460(7258):1035–1039. doi: 10.1038/nature08229. PubMed PMID: 19626005; PubMed Central PMCID: PMCPMC2956120.

  21. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94(4):491–501. PubMed PMID: 9727492.

    Article  CAS  PubMed  Google Scholar 

  22. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996;274(5288):782–4. PubMed PMID: 8864118.

    Article  CAS  PubMed  Google Scholar 

  23. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992;69(1):119–28. PubMed PMID: 1555236.

    Article  CAS  PubMed  Google Scholar 

  24. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993;362(6423):849–52. PubMed PMID: 8479523.

    Article  CAS  PubMed  Google Scholar 

  25. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993;362(6423):847–9. PubMed PMID: 8479522.

    Article  CAS  PubMed  Google Scholar 

  26. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74(6):957–67. PubMed PMID: 8402885.

    Article  CAS  PubMed  Google Scholar 

  27. Jackson JG, Pant V, Li Q, Chang LL, Quintas-Cardama A, Garza D, et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell. 2012;21(6):793–806. doi:10.1016/j.ccr.2012.04.027. PubMed PMID: 22698404; PubMed Central PMCID: PMCPMC3376352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, et al. Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat. 2012;132(3):1049–62. doi:10.1007/s10549-011-1895-2. PubMed PMID: 22198468; PubMed Central PMCID: PMCPMC3332388.

    Article  CAS  PubMed  Google Scholar 

  29. Certo M, Del Gaizo MV, Nishino M, Wei G, Korsmeyer S, Armstrong SA, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2006;9(5):351–65. doi:10.1016/j.ccr.2006.03.027. PubMed PMID: 16697956.

    Article  CAS  PubMed  Google Scholar 

  30. Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334(6059):1129–33. doi:10.1126/science.1206727. PubMed PMID: 22033517; PubMed Central PMCID: PMCPMC3280949.

    Article  PubMed  Google Scholar 

  31. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6. PubMed PMID: 18772397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52. doi:10.1038/nature16965. PubMed PMID: 26909576.

    Article  CAS  PubMed  Google Scholar 

  33. Basseres DS, Baldwin AS. Nuclear factor-kappaB and inhibitor of kappaB kinase pathways in oncogenic initiation and progression. Oncogene. 2006;25(51):6817–30. PubMed PMID: 17072330.

    Article  CAS  PubMed  Google Scholar 

  34. 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(1):119–27. PubMed PMID: 9918209.

    CAS  PubMed  Google Scholar 

  35. Dong QG, Sclabas GM, Fujioka S, Schmidt C, Peng B, Wu T, et al. The function of multiple IkappaB : NF-kappaB complexes in the resistance of cancer cells to Taxol-induced apoptosis. Oncogene. 2002;21(42):6510–9. PubMed PMID: 12226754.

    Article  CAS  PubMed  Google Scholar 

  36. Khanbolooki S, Nawrocki ST, Arumugam T, Andtbacka R, Pino MS, Kurzrock R, et al. Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. Mol Cancer Ther. 2006;5(9):2251–60. PubMed PMID: 16985059.

    Article  CAS  PubMed  Google Scholar 

  37. Finco TS, Westwick JK, Norris JL, Beg AA, Der CJ, Baldwin Jr AS. Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem. 1997;272(39):24113–6. PubMed PMID: 9305854.

    Article  CAS  PubMed  Google Scholar 

  38. Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(1):105–20. doi:10.1016/j.ccr.2011.12.006. PubMed PMID: 22264792; PubMed Central PMCID: PMCPMC3360958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shah SA, Potter MW, Hedeshian MH, Kim RD, Chari RS, Callery MP. PI-3′ kinase and NF-kappaB cross-signaling in human pancreatic cancer cells. J Gastrointest Surg. 2001;5(6):603–12; discussion 12-3. PubMed PMID: 12086898.

    Google Scholar 

  40. Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, Ji B, 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. PubMed PMID: 19088029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL, et al. Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther. 2002;1(14):1243–53. PubMed PMID: 12516957.

    CAS  PubMed  Google Scholar 

  42. Marten A, Zeiss N, Serba S, Mehrle S, von Lilienfeld-Toal M, Schmidt J. Bortezomib is ineffective in an orthotopic mouse model of pancreatic adenocarcinoma. Mol Cancer Ther. 2008;7(11):3624–31. PubMed PMID: 19001444.

    Article  PubMed  Google Scholar 

  43. Alberts SR, Foster NR, Morton RF, Kugler J, Schaefer P, Wiesenfeld M, et al. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a north central cancer treatment group (NCCTG) randomized phase II study. Ann Oncol. 2005;16(10):1654–61. PubMed PMID: 16085692.

    Article  CAS  PubMed  Google Scholar 

  44. Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14(14):4491–9. PubMed PMID: 18628464.

    Article  CAS  PubMed  Google Scholar 

  45. Epelbaum R, Schaffer M, Vizel B, Badmaev V, Bar-Sela G. Curcumin and gemcitabine in patients with advanced pancreatic cancer. Nutr Cancer. 2010;62(8):1137–41. doi:10.1080/01635581.2010.513802. PubMed PMID: 21058202.

    Article  CAS  PubMed  Google Scholar 

  46. Kanai M, Yoshimura K, Asada M, Imaizumi A, Suzuki C, Matsumoto S, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol. 2011;68(1):157–64. doi:10.1007/s00280-010-1470-2. PubMed PMID: 20859741.

    Article  CAS  PubMed  Google Scholar 

  47. Asher GN, Xie Y, Moaddel R, Sanghvi M, Dossou KS, Kashuba AD, et al. Randomized Pharmacokinetic Crossover Study Comparing 2 Curcumin Preparations in Plasma and Rectal Tissue of Healthy Human Volunteers. J Clin Pharmacol. 2016; doi:10.1002/jcph.806. PubMed PMID: 27503249.

    PubMed  Google Scholar 

  48. Storka A, Vcelar B, Klickovic U, Gouya G, Weisshaar S, Aschauer S, et al. Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans. Int J Clin Pharmacol Ther. 2015;53(1):54–65. doi:10.5414/CP202076. PubMed PMID: 25500488.

    Article  CAS  PubMed  Google Scholar 

  49. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28. PubMed PMID: 17508028.

    Article  CAS  PubMed  Google Scholar 

  50. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15. PubMed PMID: 18485877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69(14):5820–8. doi:10.1158/0008-5472.CAN-08-2819. PubMed PMID: 19584296; PubMed Central PMCID: PMCPMC4378690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Haddad Y, Choi W, McConkey DJ. Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines. Clin Cancer Res. 2009;15(2):532–42. PubMed PMID: 19147758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, et al. Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer. 2009;63(2):219–26. PubMed PMID: 18599154.

    Article  PubMed  Google Scholar 

  54. Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 2005;65(20):9455–62. PubMed PMID: 16230409.

    Article  CAS  PubMed  Google Scholar 

  55. Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res. 2005;11(24 Pt 1):8686–98. PubMed PMID: 16361555.

    Article  CAS  PubMed  Google Scholar 

  56. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17(4):500–3. doi:10.1038/nm.2344. PubMed PMID: 21460848; PubMed Central PMCID: PMCPMC3755490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527(7579):525–30. doi:10.1038/nature16064. PubMed PMID: 26560028; PubMed Central PMCID: PMCPMC4849281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, et al. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009;15(6):489–500. doi:10.1016/j.ccr.2009.03.022. PubMed PMID: 19477428; PubMed Central PMCID: PMCPMC2743093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Genovese G, Carugo A, Tepper J, Robinson FS, Li L, Svelto M, et al. Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. Nature. 2017;542(7641):362–6. doi:10.1038/nature21064. PubMed PMID: 28178232.

    Article  CAS  PubMed  Google Scholar 

  60. Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 2006;66(2):944–50. PubMed PMID: 16424029.

    Article  CAS  PubMed  Google Scholar 

  61. Jones SF, Bendell JC, Infante JR, Spigel DR, Thompson DS, Yardley DA, et al. A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors. Clin Adv Hematol Oncol. 2011;9(3):225–30. PubMed PMID: 21475129.

    PubMed  Google Scholar 

  62. Avan A, Crea F, Paolicchi E, Funel N, Galvani E, Marquez VE, et al. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells. Mol Cancer Ther. 2012;11(8):1735–46. doi:10.1158/1535-7163.MCT-12-0037. PubMed PMID: 22622284; PubMed Central PMCID: PMCPMC3416916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47(10):1168–78. doi:10.1038/ng.3398. PubMed PMID: 26343385; PubMed Central PMCID: PMCPMC4912058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Vonlaufen A, Phillips PA, Xu Z, Goldstein D, Pirola RC, Wilson JS, et al. Pancreatic stellate cells and pancreatic cancer cells: an unholy alliance. Cancer Res. 2008;68(19):7707–10. PubMed PMID: 18829522.

    Article  CAS  PubMed  Google Scholar 

  65. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68(3):918–26. PubMed PMID: 18245495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61. doi:10.1126/science.1171362. PubMed PMID: 19460966; PubMed Central PMCID: PMCPMC2998180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim EJ, Sahai V, Abel EV, Griffith KA, Greenson JK, Takebe N, et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin Cancer Res. 2014;20(23):5937–45. doi:10.1158/1078-0432.CCR-14-1269. PubMed PMID: 25278454; PubMed Central PMCID: PMCPMC4254161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, et al. Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer. J Clin Oncol. 2015;33(36):4284–92. doi:10.1200/JCO.2015.62.8719. PubMed PMID: 26527777; PubMed Central PMCID: PMCPMC4678179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–47. doi:10.1016/j.ccr.2014.04.021. PubMed PMID: 24856585; PubMed Central PMCID: PMCPMC4096698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–34. doi:10.1016/j.ccr.2014.04.005. PubMed PMID: 24856586; PubMed Central PMCID: PMCPMC4180632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med. 2016;22(5):497–505. doi:10.1038/nm.4082. PubMed PMID: 27089513; PubMed Central PMCID: PMCPMC4860133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Johns Hopkins Greenberg Bladder Cancer Institute, 600 N Wolfe Street/Marburg 149, Baltimore, MD, 21287, USA

    David J. McConkey

  2. Department of Urology, Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA

    David J. McConkey

  3. Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Woonyoung Choi

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  1. David J. McConkey
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  2. Woonyoung Choi
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Correspondence to David J. McConkey .

Editor information

Editors and Affiliations

  1. DMCCMC, University of Liverpool DMCCMC, Liverpool, United Kingdom

    John P. Neoptolemos

  2. Rochester, Minnesota, USA

    Raul Urrutia

  3. Dept. Gastrointestinal Medical Onco, Duke University Medical Center Dept. Gastrointestinal Medical Onco, Durham, North Carolina, USA

    James Abbruzzese

  4. Heidelberg, Germany

    Markus W. Büchler

Section Editor information

  1. Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA

    Raul A. Urrutia

  2. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Markus W. Büchler MD

  3. Division of Surgery and Oncology, University of Liverpool, Daulby Street, Liverpool, UK

    John Neoptolemos

  4. Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Thilo Hackert MD

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McConkey, D.J., Choi, W. (2017). Apoptosis: Signaling Pathways in Pancreatic Cancer Pathogenesis. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6631-8_14-2

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  • DOI: https://doi.org/10.1007/978-1-4939-6631-8_14-2

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