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Prognostic significance of WNT signaling in pancreatic ductal adenocarcinoma

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies and is associated with a variety of molecular abnormalities. Although WNT signaling through its canonical/non-canonical pathways is one of the major factors involved in oncogenesis or progression of PDA, the prognostic significance of WNT signaling still remains poorly investigated. In this study, the status of the WNT signaling pathways was immunohistochemically analyzed in 101 PDAs, and its potential association with patient postoperative survival was assessed. Nuclear expression of beta-catenin, a hallmark of the activated canonical pathway, was identified in 59 cases, and was associated with reduced survival compared to the patients lacking nuclear beta-catenin expression (P = 0.002). In contrast, activation of the non-canonical pathway (25 cases), as indicated by co-expression of WNT2/5a and nuclear NFATc1, was not correlated with reduced survival (P = 0.268). Co-activation of both pathways (16 cases) was associated with worse prognosis in comparison with cases with an activated non-canonical pathway (P = 0.034). In addition, nuclear beta-catenin expression was an independent unfavorable prognostic factor (P = 0.006). Our data indicate that activated WNT signaling through its canonical pathway has a significantly negative effect on the clinical course of PDA, and the canonical WNT pathway should be considered as a future therapeutic target for PDA.

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References

  1. Cress RD, Yin D, Clarke L, Bold R, Holly EA (2006) Survival among patients with adenocarcinoma of the pancreas: a population-based study (United States). Cancer Causes Control 17:403–409. doi:10.1007/s10552-005-0539-4

    Article  PubMed  Google Scholar 

  2. Winter JM, Brennan MF, Tang LH, D’Angelica MI, Dematteo RP, FongY KDS, Jamagin WR, Allen PJ (2012) Survival after resection of pancreatic adenocarcinoma: results from a single institution over three decades. Ann Surg Oncol 19:169–175. doi:10.1245/s10434-011-1900-3

    Article  PubMed  Google Scholar 

  3. Miura T, Hirano S, Nakamura T, Tanaka E, Shichinohe T, Tsuchikawa T, Kato K, Matsumoto J, Kondo S (2014) A new preoperative prognostic scoring system to predict prognosis in patients with locally advanced pancreatic body cancer who undergo distal pancreatectomy with en bloc celiac axis resection: a retrospective cohort study. Surgery 155:457–467. doi:10.1016/j.surg.2013.10.024

    Article  PubMed  Google Scholar 

  4. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378:607–620. doi:10.1016/S0140-6736(10)62307-0

    Article  PubMed  Google Scholar 

  5. Longo R, Cacciamani F, Naso G, Gasparini G (2008) Pancreatic cancer: form molecular signature to target therapy. Crit Rev Oncol Hematol 68:197–211. doi:10.1016/j.critrevonc.2008.03.003

    Article  PubMed  CAS  Google Scholar 

  6. Xiao W, Hong H, Awadallah A, Zhou L, Xin W (2014) Utilization of CDX2 expression in diagnosing pancreatic ductal adenocarcinoma and predicting prognosis. PLoS ONE 9:e86853. doi:10.1371/journal.pone.0086853

    Article  PubMed  PubMed Central  Google Scholar 

  7. Denley S, Jamieson NB, McCall P, Oien KA, Morton JP, Carter CR, Edwards J, McKay CJ (2013) Activation of the IL-6R/Jak/Stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. J Gastrointest Surg 17:887–898. doi:10.1007/s11605-013-2168-7

    Article  PubMed  Google Scholar 

  8. Mann CD, Bastianpillai C, Neal CP, Masood MM, Jones DJ, Teichert F, Singh R, Karpova E, Berry DP, Manson MM (2012) Notch3 and Hey-1 as prognostic biomarkers in pancreatic adenocarcinoma. PLoS ONE 7:e51119. doi:10.1371/journal.pone.0051119

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Clevers H (2006) Wnt/β-catenin signaling in development and disease. Cell 127:469–480. doi:10.1016/j.cell.2006.10.018

    Article  PubMed  CAS  Google Scholar 

  10. Hu T, Li C (2010) Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol Cancer 9:236–242. doi:10.1186/1476-4598-9-236

    Article  PubMed  PubMed Central  Google Scholar 

  11. Katoh M, Katoh M (2007) WNT signaling pathway and stem cell signaling network. Clin Cancer Res 13:4042–4045. doi:10.1158/1078-0432.CCR-06-2316

    Article  PubMed  CAS  Google Scholar 

  12. Schwartz AL, Malgor R, Dickerson E, Weeraratna AT, Slominski A, Wortsman J, Haril N, Kohn AD, Moor RT, Schwartz FL, Goetz DJ, Kohn LD, McCall KD (2009) Phenylmethimazole decrease toll-like receptor 3 and noncanonical WNT5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res 15:4114–4122. doi:10.1158/1078-0432.CCR-09-0005

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Yu M, Ting DT, Stott SL, Wittner BS, Ozsolak F, Paul S, Ciciliano JC, Smas ME, Winokur D, Gilman AJ, Ulman AJ, Xega K, Contino G, Alagesan B, Brannigan BW, Milos PM, Ryan DP, Sequist LV, Bardeesy N, Ramaswamy S, Toner M, Maheswaran S, Haber DA (2012) RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 487:510–513. doi:10.1038/nature11217

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A, Malhotra V, Sood N, Midda V, Monga DK, Kokkinakis DM, Monga SP (2006) Aberrant Wnt/β-catenin signaling in pancreatic adenocarcinoma. Neoplasia 8:279–289. doi:10.1593/neo.05607

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. di Magliano MP, Biankin AV, Heiser PW, Cano DA, Gutierrez PJA, 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:e1155. doi:10.1371/journal.pone.0001155

    Article  Google Scholar 

  16. Zhang Y, Morris JP 4th, Yan W, Schofield HK, Gumey A, Simeone DM, Millar SE, Hoey T, Hebrok M, di Magliano MP (2013) Canonical Wnt signaling is required for pancreatic carcinogenesis. Cancer Res 73:4909–4922. doi:10.1158/0008-5472.CAN-12-4384

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Hruban RH, Boffetta P, Hiraoka N, Iacobuzio-Donahue C, Kato Y, Kern SE, Klimstra DS (2010) Ductal adenocarcinoma of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumours of the digestive system. IARC Press, Lyon, pp 281–291

    Google Scholar 

  18. Sobin LH, Gospodarowicz MK, Wittekind C (2009) TNM classification of malignant tumours, 7th edn. Wiley-Blackwell, Oxford

    Google Scholar 

  19. Mancini M, Toker A (2009) NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 9:810–820. doi:10.1038/nrc2735

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Griesmann H, Ripka S, Pralle M, Ellenrieder V, Baumgart S, Buchholz M, Pilarsky C, Aust D, Gress TM, Michl P (2013) WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic cancer. Neoplasia 15:11–22. doi:10.1593/neo.121312

    PubMed  CAS  PubMed Central  Google Scholar 

  21. Gerdes B, Rmanswamy A, Simon B, Pietsch T, Bastian D, Kersting M, Moll R, Bartsch D (1999) Analysis of beta-catenin gene mutations in pancreatic tumors. Digestion 60:544–548. doi:10.1159/000007704

    Article  PubMed  CAS  Google Scholar 

  22. 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 160:1361–1369. doi:10.1016/S0002-9440(10)62563-1

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Brennan K, Gonzalez-Sancho JM, Castelo-Soccio LA, Howe LR, Brown AMC (2004) Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize β-catenin independently of Frizzled proteins. Oncogene 23:4873–4884. doi:10.1038/sj.onc.1207642

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M (2011) Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res 17:4341–4354. doi:10.1158/1078-0432.CCR-10-3431

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Arensman MD, Kovochich AN, Kulikauskas RM, Lay AR, Yang PT, Li X, Donahue T, Major MB, Moon RT, Chien AJ, Dawson DW (2014) WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma. Oncogene 33:899–908. doi:10.1038/onc.2013.23

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Li YJ, Wei ZM, Meng YX, Ji XR (2005) Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationship with carcinogenesis and metastases. World J Gastroenterol 11:2117–123

    PubMed  CAS  Google Scholar 

  27. Qiao Q, Ramadani M, Gansauge S, Gansauge F, Leder G, Beger HG (2001) Reduced membranous and ectopic cytoplasmic expression of beta-catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer. Int J Cancer 95:194–197

    Article  PubMed  CAS  Google Scholar 

  28. White BD, Chien AJ, Dawson DW (2012) Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology 142:219–232. doi:10.1053/j.gastro.2011.12.001

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Ripka S, König A, Buchholz M, Wagner M, Sipos B, Klöppel G, Downward J, Gress TM, Michl P (2007) WNT5a—target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis 28:1178–1187. doi:10.1093/carcin/bgl255

    Article  PubMed  CAS  Google Scholar 

  30. Yiu GK, Kaunisto A, Chin YR, Toker A (2011) NFAT promotes carcinoma invasive migration through glypican-6. Biochem J 440:157–166. doi:10.1042/BJ20110530

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Grossmann TN, Yeh JTH, Bowman BR, Chu Q, Moellering RE, Verdine GL (2014) Inhibition of oncogenic Wnt signaling through direct targeting of b-catenin. Proc Natl Acad Sci U S A 109:17942–17947. doi:10.1073/pnas.1208396109

    Article  Google Scholar 

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Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan

    Mitsuhiro Nakamoto, Ryo Shibuya, Takahiko Kasai & Masanori Hisaoka

  2. Department of Surgery 1, School of Medicine, University Hospital, University of Occupational and Environmental Health, Kitakyushu, Japan

    Mitsuhiro Nakamoto & Koji Yamaguchi

  3. Department of Surgical Pathology, University Hospital, University of Occupational and Environmental Health, Kitakyushu, Japan

    Atsuji Matsuyama, Eisuke Shiba & Masanori Hisaoka

Authors
  1. Mitsuhiro Nakamoto
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  2. Atsuji Matsuyama
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  3. Eisuke Shiba
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  4. Ryo Shibuya
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  5. Takahiko Kasai
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  7. Masanori Hisaoka
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Correspondence to Masanori Hisaoka.

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Nakamoto, M., Matsuyama, A., Shiba, E. et al. Prognostic significance of WNT signaling in pancreatic ductal adenocarcinoma. Virchows Arch 465, 401–408 (2014). https://doi.org/10.1007/s00428-014-1642-2

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  • DOI: https://doi.org/10.1007/s00428-014-1642-2

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