Smad4-TGF-β Signaling Pathways in Pancreatic Cancer Pathogenesis

Reference work entry

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a 9% 5-year survival rate. For reasons that are not readily evident, KRAS is mutated in 90–95% of PDAC cases, and this truncal alteration is associated with a high frequency of mutations in crucially important tumor suppressor genes, most notably CDKN2A (~90%), a gene that encodes p16, TP53 (~70%), and SMAD4 (~50%). Concomitantly, there is overexpression of transforming growth factor beta (TGF-β) isoforms and of high-affinity tyrosine kinase receptors (TKRs) and their ligands. Enhanced cancer cell proliferation and migration mediated by TKRs, combined with loss of beneficial TGF-β-dependent pathways required to restrain uncontrolled cell proliferation, contributes to PDAC’s biological aggressiveness. This chapter provides an overview of these issues and focuses on the role of alterations in Smad4 expression and function and aberrant TGF-β signaling that combine to promote pancreatic cancer growth through cell autonomous and paracrine actions, thereby contributing in an important manner to PDAC pathobiology.

Keywords

Smad4 Smad7 TGF-β Canonical signaling Non-canonical signaling Tumor microenvironment Pancreatic cancer Angiogenesis TGF-β 

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2017;67:7–30.PubMedCrossRefGoogle Scholar
  2. 2.
    Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. J Am Med Assoc. 2015;314:1021–9.CrossRefGoogle Scholar
  3. 3.
    Aggarwal G, Kamada P, Chari S. Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas. 2013;42:198–201.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Tang H, Dong X, Hassan M, Abbruzzese JL, Li D. Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer. Cancer Epidemiol Biomark Prev. 2011;20:779–92.CrossRefGoogle Scholar
  5. 5.
    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:1039–49.PubMedCrossRefGoogle Scholar
  7. 7.
    Paulson AS, Tran Cao HS, Tempero MA, Lowy AM. Therapeutic advances in pancreatic cancer. Gastroenterology. 2013;144:1316–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006;20:1218–49.PubMedCrossRefGoogle Scholar
  9. 9.
    Preis M, Korc M. Signaling pathways in pancreatic cancer. Crit Rev Eukaryot Gene Expr. 2011;21:115–29.PubMedCrossRefGoogle Scholar
  10. 10.
    Provenzano PP, Cuevas C, Chang AE, Goel K, Von Hoff D, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418–29.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.PubMedCrossRefGoogle Scholar
  12. 12.
    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. 2001;321:1801–6.CrossRefGoogle Scholar
  13. 13.
    Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994;8:133–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, Nohe A. Bone morphogenetic proteins: a critical review. Cell Signal. 2011;23(4):609–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Wu MY, Hill CS. TGF-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009;16:329–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Gold L. The role for transforming growth factor-beta (TGF-beta) in human cancer. Clin Rev Oncog. 1999;10:303–60.Google Scholar
  19. 19.
    Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.PubMedCrossRefGoogle Scholar
  20. 20.
    Weiss A, Attisano L. The TGFbeta superfamily signaling pathway. Rev Dev Biol. 2013;2:47–63.Google Scholar
  21. 21.
    Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19:2783–810.PubMedCrossRefGoogle Scholar
  22. 22.
    Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell. 1998;95:779–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Feng XH, Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Holtzhausen A, Golzio C, How T, Lee YH, Schiemann WP, Katsanis N, et al. Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development. FASEB J. 2014;28:1248–67.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Nicolás FJ, De Bosscher K, Schmierer B, Hill CS. Analysis of Smad nucleocytoplasmic shuttling in living cells. J Cell Sci. 2004;117:4113–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Germain S, Howell M, Esslemont GM, Hill CS. Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev. 2000;14:435–51.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Hill CS. Transcriptional control by the SMADs. Cold Spring Harb Perspect Biol. 2016;8(10). pii: a022079.  https://doi.org/10.1101/cshperspect.a022079.
  28. 28.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.PubMedCrossRefGoogle Scholar
  29. 29.
    Dai F, Shen T, Li Z, Lin X, Feng XH. PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3. EMBO Rep. 2011;12:1175–81.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Watanabe M, Masuyama N, Fukuda M, Nishida E. Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep. 2000;1:176–82.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, et al. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci USA. 1997;94:9314–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276:12477–80.PubMedCrossRefGoogle Scholar
  33. 33.
    Ogunjimi AA, Briant DJ, Pece-Barbara N, Le Roy C, Di Guglielmo GM, Kavsak P, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell. 2005;19:297–308.PubMedCrossRefGoogle Scholar
  34. 34.
    Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, et al. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med. 2012;18:429–35.PubMedCrossRefGoogle Scholar
  35. 35.
    Shi W, Sun C, He B, Xiong W, Shi X, Yao D, et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol. 2004;164:291–300.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, et al. Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling. J Biol Chem. 2009;284:30097–104.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, et al. Arkadia induces degradation of SnoN and c-ski to enhance transforming growth factor-beta signaling. J Biol Chem. 2007;282:20492–501.PubMedCrossRefGoogle Scholar
  38. 38.
    Lonn P, van der Heide LP, Dahl M, Hellman U, Heldin CH, Moustakas A. PARP-1 attenuates Smad-mediated transcription. Mol Cell. 2010;40:521–32.PubMedCrossRefGoogle Scholar
  39. 39.
    Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu A, et al. Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene. 2007;26:500–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Eifler K, Vertegaal AC. SUMOylation-mediated regulation of cell cycle progression and cancer. Trends Biochem Sci. 2015;40:779–93.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Yamanaka Y, Friess H, Buchler M, Beger HG, Gold LI, Korc M. Synthesis and expression of transforming growth factor beta-1, beta-2, and beta-3 in the endocrine and exocrine pancreas. Diabetes. 1993;42:746–56.PubMedCrossRefGoogle Scholar
  42. 42.
    Bottinger EP, Jakubczak JL, Roberts IS, Mumy M, Hemmati P, Bagnall K, et al. Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas. EMBO J. 1997;16:2621–33.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wildi S, Kleeff J, Mayerle J, Zimmermann A, Bottinger EP, Wakefield L, et al. Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations. Gut. 2007;56:685–92.PubMedCrossRefGoogle Scholar
  44. 44.
    Chaudhury A, Howe PH. The tale of transforming growth factor-beta (TGFbeta) signaling: a soigné enigma. IUBMB Life. 2009;61:929–39.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Baldwin RL, Korc M. Growth inhibition of human pancreatic carcinoma cells by transforming growth factor beta-1. Growth Factors. 1993;8:23–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Grady WM, Myeroff LL, Swinler SE, Rajput A, Thiagalingam S, Lutterbaugh JD, et al. Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res. 1999;59:320–4.PubMedGoogle Scholar
  48. 48.
    Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 1998;58:5329–32.PubMedGoogle Scholar
  49. 49.
    Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Xu J, Attisano L. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA. 2000;97:4820–5.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kleeff J, Maruyama H, Friess H, Buchler MW, Falb D, Korc M. Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer. Biochem Biophys Res Commun. 1999;255:268–73.PubMedCrossRefGoogle Scholar
  52. 52.
    Kleeff J, Ishiwata T, Maruyama H, Friess H, Truong P, Büchler MW, et al. The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene. 1999;18:5363–72.PubMedCrossRefGoogle Scholar
  53. 53.
    Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57:3126–30.PubMedGoogle Scholar
  54. 54.
    Carrière C, Gore AJ, Norris AM, Gunn JR, Young AL, Longnecker DS, et al. Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions. Gastroenterology. 2011;141:1091–101.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Gore AJ, Deitz SL, Palam LR, Craven KE, Korc M. Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. J Clin Invest. 2014;124:338–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Ambros V. microRNAs: tiny regulators with great potential. Cell. 2001;107:823–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.PubMedCrossRefGoogle Scholar
  58. 58.
    Hirata H, Ueno K, Shahryari V, Tanaka Y, Tabatabai ZL, Hinoda Y, et al. Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer. PLoS One. 2012;7:e51056.  https://doi.org/10.1371/journal.pone.0051056.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Zhang Y, Fan KJ, Sun Q, Chen AZ, Shen WL, Zhao ZH, et al. Functional screening for miRNAs targeting Smad4 identified miR-199a as a negative regulator of TGF-β signalling pathway. Nucleic Acids Res. 2012;40:9286–97.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Wang Y, Ren J, Gao Y, Ma JZ, Toh HC, Chow P, et al. MicroRNA-224 targets SMAD family member 4 to promote cell proliferation and negatively influence patient survival. PLoS One. 2013;8(7):e68744.  https://doi.org/10.1371/journal.pone.0068744.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hao J, Zhang S, Zhou Y, Liu C, Hu X, Shao C. MicroRNA 421 suppresses DPC4/Smad4 in pancreatic cancer. Biochem Biophys Res Commun. 2011;406:552–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Hao J, Zhang S, Zhou Y, Hu X, Shao C. MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer. FEBS Lett. 2011;585:207–13.PubMedCrossRefGoogle Scholar
  63. 63.
    Xia X, Zhang K, Cen G, Jiang T, Cao J, Huang K, et al. MicroRNA-301a-3p promotes pancreatic cancer progression via negative regulation of SMAD4. Oncotarget. 2015;6:21046–63.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Li L, Li Z, Kong X, Xie D, Jia Z, Jiang W, et al. Down-regulation of microRNA-494 via loss of SMAD4 increases FOXM1 and β-catenin signaling in pancreatic ductal adenocarcinoma cells. Gastroenterology. 2014;147:485–97.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhong X, Chung AC, Chen HY, Meng XM, Lan HY. Smad3-mediated upregulation of miR-21 promotes renal fibrosis. J Am Soc Nephrol. 2011;22:1668–81.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA- mediated microRNA maturation. Nature. 2008;454:56–61.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Sempere LF, Preis M, Yezefski T, Ouyang H, Suriawinata AA, Silahtaroglu A, et al. Fluorescence-based codetection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumors. Clin Cancer Res. 2010;16:4246–55.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010;467:86–90.PubMedCrossRefGoogle Scholar
  69. 69.
    Thornley JA, Trask HW, Ringelberg CS, Ridley CJ, Wang S, Sal-Lari RC, et al. SMAD4-dependent polysome RNA recruitment in human pancreatic cancer cells. Mol Carcinog. 2012;51:771–82.PubMedCrossRefGoogle Scholar
  70. 70.
    Wang J, Shao N, Ding X, Tan B, Song Q, Wang N, et al. Crosstalk between transforming growth factor-β signaling pathway and long non-coding RNAs in cancer. Cancer Lett. 2016;370:296–301.PubMedCrossRefGoogle Scholar
  71. 71.
    Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81.PubMedCrossRefGoogle Scholar
  72. 72.
    Xu X, Brodie SG, Yang X, Im YH, Parks WT, Chen L, et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene. 2000;19:1868–74.PubMedCrossRefGoogle Scholar
  73. 73.
    Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, et al. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev. 1998;12:107–19.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Duda DG, Sunamura M, Lefter LP, Furukawa T, Yokoyama T, Yatsuoka T, et al. Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells. Oncogene. 2003;22:6857–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA. 2000;97:9624–9.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Yasutome M, Gunn J, Korc M. Restoration of Smad4 in BxPC3 pancreatic cancer cells attenuates proliferation without altering angiogenesis. Clin Exp Metastasis. 2005;22:461–73.PubMedCrossRefGoogle Scholar
  77. 77.
    Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.CrossRefPubMedGoogle Scholar
  78. 78.
    Pérez-Mancera PA, Guerra C, Barbacid M, Tuveson DA. What we have learned about pancreatic cancer from mouse models. Gastroenterology. 2012;142:1079–92.PubMedCrossRefGoogle Scholar
  79. 79.
    Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20:3130–46.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Ardito CM, Grüner BM, Takeuchi KK, Lubeseder-Martellato C, Teichmann N, Mazur PK, et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell. 2012;22:304–17.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Norris AM, Gore A, Balboni A, Young A, Longnecker DS, Korc M. AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene. 2013;32:3867–76.PubMedCrossRefGoogle Scholar
  82. 82.
    Lin L, Tu HB, Wu L, Liu M, Jiang GN. MicroRNA-21 regulates non-small cell lung cancer cell invasion and chemo-sensitivity through SMAD7. Cell Physiol Biochem. 2016;38:2152–62.PubMedCrossRefGoogle Scholar
  83. 83.
    Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC, et al. The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene. 2012;31:5162–71.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Yu J, Lei R, Zhuang X, Li X, Li G, Lev S, et al. MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells. Nat Commun. 2016;7:13884.  https://doi.org/10.1038/ncomms13884.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, et al. Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells. Nat Biothechnol. 2011;29:443–8.CrossRefGoogle Scholar
  86. 86.
    Yan X, Chen YG. Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling. Biochem J. 2011;434:1–10.PubMedCrossRefGoogle Scholar
  87. 87.
    Arnold NB, Ketterer K, Kleeff J, Friess H, Buchler MW, Korc M. Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer. Cancer Res. 2004;64:3599–606.PubMedCrossRefGoogle Scholar
  88. 88.
    Boyer Arnold N, Korc M. Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein. J Biol Chem. 2005;280:21858–66.PubMedCrossRefGoogle Scholar
  89. 89.
    Friess H, Yamanaka Y, Buchler M, Ebert M, Beger HG, Gold LI, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;105:1846–56.PubMedCrossRefGoogle Scholar
  90. 90.
    Aikawa T, Gunn J, Spong SM, Klaus SJ, Korc M. Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer. Mol Cancer Ther. 2006;5:1108–16.PubMedCrossRefGoogle Scholar
  91. 91.
    Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc Natl Acad Sci USA. 2013;110:12325–30.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Lawler S, Feng XH, Chen RH, Maruoka EM, Turck CW, Griswold-Prenner I, et al. The type II transforming growth factor-beta receptor autophosphorylates not only on serine and threonine but also on tyrosine residues. J Biol Chem. 1997;272:14850–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Lee MK, Pardoux C, Hall MC, Lee PS, Warburton D, Qing J, et al. TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBO J. 2007;26:3957–67.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol. 2008;10:1199–207.PubMedCrossRefGoogle Scholar
  95. 95.
    Zhong Y, Naito Y, Cope L, Naranjo-Suarez S, Saunders T, Hong SM, et al. Functional p38 MAPK identified by biomarker profiling of pancreatic cancer restrains growth through JNK inhibition and correlates with improved survival. Clin Cancer Res. 2014;20:6200–11.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Zhang H, Davies KJ, Forman HJ. TGFβ1 rapidly activates Src through a non-canonical redox signaling mechanism. Arch Biochem Biophys. 2015;568:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hoefer M, Anderer FA. Anti-transforming growth factor beta antibodies with predefined specificity inhibit metastasis of highly tumorigenic human xenotransplants in nu/nu mice. Cancer Immunol Immunother. 1995;41:302–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Marzo AL, Fitzpatrick DR, Robinson BW, Scott B. Antisense oligonucleotides specific for transforming growth factor beta2 inhibit the growth of malignant mesothelioma both in vitro and in vivo. Cancer Res. 1997;57:3200–7.PubMedGoogle Scholar
  99. 99.
    Lopez AR, Cook J, Deininger PL, Derynck R. Dominant negative mutants of transforming growth factor-beta 1 inhibit the secretion of different transforming growth factor-beta isoforms. Mol Cell Biol. 1992;12:1674–9.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Rowland-Goldsmith MA, Maruyama H, Kusama T, Ralli S, Korc M. 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. 2001;7:2931–40.PubMedGoogle Scholar
  101. 101.
    Nam J-S, Terabe M, Mamura M, Kang M-J, Chae H, Stuelten C, et al. An anti-transforming growth factor β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 2008;68:3835–43.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Connolly EC, Saunier EF, Quigley D, Luu MT, De Sapio A, Hann B, et al. Outgrowth of drug-resistant carcinomas expressing markers of tumor aggression after long-term TβRI/II kinase inhibition with LY2109761. Cancer Res. 2011;71:2339–49.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Hezel AF, Deshpande V, Zimmerman SM, Contino G, Alagesan B, O’Dell MR, et al. TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression. Cancer Res. 2012;72:4840–5.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, et al. TGF-β tumor suppression through a lethal EMT. Cell. 2016;164:1015–30.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Craven KE, Gore J, Wilson JL, Korc M. Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes. Oncotarget. 2016;7:323–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departments of Medicine, Biochemistry and Molecular BiologyIndiana University School of Medicine, the Melvin and Bren Simon Cancer Center and the Pancreatic Cancer Signature CenterIndianapolisUSA

Section editors and affiliations

  • Raul Urrutia
    • 1
  • M. W. Büchler
    • 2
  • John P. Neoptolemos
    • 3
    • 4
    • 5
  • Th. Hackert
    • 6
  1. 1.GI Research Unit, Mayo ClinicRochesterUSA
  2. 2.Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
  3. 3.Department of SurgeryThe Royal Liverpool and Broadgreen University Hospitals NHS TrustLiverpoolUK
  4. 4.Department of Molecular and Clinical Cancer Medicine, Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK
  5. 5.NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer MedicineUniversity of LiverpoolLiverpoolUK
  6. 6.Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany

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