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Claudin-4 Expression Predicts Survival in Pancreatic Ductal Adenocarcinoma

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Identification of prognostic markers would be useful in the clinical management of patients with pancreatic ductal adenocarcinoma (PDAC). The clinical relevance of claudin-4 (CLDN4), recently identified as overexpressed in PDAC, is unknown.

Methods

Using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), we analyzed CLDN4 mRNA expression in a panel of 9 pancreatic cancer cell lines and formalin-fixed paraffin-embedded (FFPE) tissues from 100 patients with PDAC. The CLDN4 expression levels were then correlated with clinicopathological variables and patient outcome. We also performed immunohistochemical analysis in 20 FFPE samples of PDAC to investigate the expression of CLDN4 protein.

Results

Increased expression of CLDN4 was confirmed in all the pancreatic cancer cell lines tested compared with normal ductal epithelial cells and fibroblasts. We found that low expression of CLDN4 was significantly associated with shorter survival in patients with PDAC (hazard ratio; 1.362, 95% confidence interval; 1.011–1.873, P = 0.0419). Patients with high CLDN4 expression survived longer for a median of 63.0 months, compared with 14.7 months in patients with low CLDN4 expression (P = 0.0067). In immunohistochemical analysis, the level of CLDN4 mRNA expression was significantly correlated with the expression of CLDN4 protein (P = 0.0168).

Conclusion

Increased expression of CLDN4 mRNA predicts better prognosis in PDAC.

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References

  1. Eskelinen MJ, Haglund UH. Prognosis of human pancreatic adenocarcinoma: review of clinical and histopathological variables and possible uses of new molecular methods. Eur J Surg. 1999;165:292–306.

    Article  PubMed  CAS  Google Scholar 

  2. Yeo TP, Hruban RH, Leach SD, Wilentz RE, Sohn TA, Kern SE, et al. Pancreatic cancer. Curr Probl Cancer. 2002;26:176–275.

    Article  PubMed  Google Scholar 

  3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.

    Article  PubMed  Google Scholar 

  4. Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91:586–94.

    Article  PubMed  CAS  Google Scholar 

  5. Carpelan-Holmstrom M, Nordling S, Pukkala E, Sankila R, Luttges J, Kloppel G, et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut. 2005;54:385–7.

    Article  PubMed  CAS  Google Scholar 

  6. Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg. 2006;244:10–5.

    Article  PubMed  Google Scholar 

  7. Ferrone CR, Finkelstein DM, Thayer SP, Muzikansky A, Fernandez-delCastillo C, Warshaw AL. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol. 2006;24:2897–902.

    Article  PubMed  CAS  Google Scholar 

  8. Muller MW, Friess H, Koninger J, Martin D, Wente MN, Hinz U, et al. Factors influencing survival after bypass procedures in patients with advanced pancreatic adenocarcinomas. Am J Surg. 2008;195:221–8.

    Article  PubMed  Google Scholar 

  9. Kondo N, Murakami Y, Uemura K, Hayashidani Y, Sudo T, Hashimoto Y, et al. Prognostic impact of perioperative serum CA 19-9 levels in patients with resectable pancreatic cancer. Ann Surg Oncol. 2010;17:2321–9.

    Article  PubMed  Google Scholar 

  10. Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15:4674–9.

    Article  PubMed  CAS  Google Scholar 

  11. Sinicrope FA, Evans DB, Leach SD, Cleary KR, Fenoglio CJ, Lee JJ, et al. bcl-2 and p53 expression in resectable pancreatic adenocarcinomas: association with clinical outcome. Clin Cancer Res. 1996;2:2015–22.

    PubMed  CAS  Google Scholar 

  12. Nio Y, Dong M, Iguchi C, Yamasawa K, Toga T, Itakura M, et al. Expression of Bcl-2 and p53 protein in resectable invasive ductal carcinoma of the pancreas: effects on clinical outcome and efficacy of adjuvant chemotherapy. J Surg Oncol. 2001;76:188–96.

    Article  PubMed  CAS  Google Scholar 

  13. Yamamoto H, Itoh F, Iku S, Adachi Y, Fukushima H, Sasaki S, et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J Clin Oncol. 2001;19:1118–27.

    PubMed  CAS  Google Scholar 

  14. Jones LE, Humphreys MJ, Campbell F, Neoptolemos JP, Boyd MT. Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin Cancer Res. 2004;10:2832–45.

    Article  PubMed  CAS  Google Scholar 

  15. Gerdes B, Ramaswamy A, Ziegler A, Lang SA, Kersting M, Baumann R, et al. p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb. Ann Surg. 2002;235:51–9.

    Article  PubMed  Google Scholar 

  16. Joo YE, Rew JS, Park CS, Kim SJ. Expression of E-cadherin, alpha- and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology. 2002;2:129–37.

    Article  PubMed  CAS  Google Scholar 

  17. Niedergethmann M, Hildenbrand R, Wostbrock B, Hartel M, Sturm JW, Richter A, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas. 2002;25:122–9.

    Article  PubMed  Google Scholar 

  18. Kuwahara K, Sasaki T, Kuwada Y, Murakami M, Yamasaki S, Chayama K. Expressions of angiogenic factors in pancreatic ductal carcinoma: a correlative study with clinicopathologic parameters and patient survival. Pancreas. 2003;26:344–9.

    Article  PubMed  CAS  Google Scholar 

  19. Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP. Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer. 2005;41:2213–36.

    Article  PubMed  CAS  Google Scholar 

  20. Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006;66:3928–35.

    Article  PubMed  CAS  Google Scholar 

  21. Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Fujita H, Nakata K, et al. S100A4 mRNA is a diagnostic and prognostic marker in pancreatic carcinoma. J Gastrointest Surg. 2009;13:1852–8.

    Article  PubMed  Google Scholar 

  22. Hough CD, Sherman-Baust CA, Pizer ES, Montz FJ, Im DD, Rosenshein NB, et al. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res. 2000;60:6281–7.

    PubMed  CAS  Google Scholar 

  23. Long H, Crean CD, Lee WH, Cummings OW, Gabig TG. Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium. Cancer Res. 2001;61:7878–81.

    PubMed  CAS  Google Scholar 

  24. Kominsky SL, Vali M, Korz D, Gabig TG, Weitzman SA, Argani P, et al. Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol. 2004;164:1627–33.

    Article  PubMed  CAS  Google Scholar 

  25. Ryu B, Jones J, Hollingsworth MA, Hruban RH, Kern SE. Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. Cancer Res. 2001;61:1833–8.

    PubMed  CAS  Google Scholar 

  26. Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol. 2003;162:1151–62.

    Article  PubMed  CAS  Google Scholar 

  27. Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer. 2006;6:186.

    Article  PubMed  Google Scholar 

  28. Michl P, Barth C, Buchholz M, Lerch MM, Rolke M, Holzmann KH, et al. Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res. 2003;63:6265–71.

    PubMed  CAS  Google Scholar 

  29. Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, et al. Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 2004;64:3215–22.

    Article  PubMed  CAS  Google Scholar 

  30. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115: 421–32.

    Article  PubMed  CAS  Google Scholar 

  31. Hruban RH, Boffetta P, Hiraoka N, et al. Ductal adenocarcinoma of the pancreas. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. Lyon, France: IARC Press; 2010. p. 281–91.

  32. Sobin L, Wittekind C. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. In: TNM Classification of Malignant Tumors. 6th ed. New York: Wiley-Liss; 2002.

  33. Ohuchida K, Mizumoto K, Ogura Y, Ishikawa N, Nagai E, Yamaguchi K, et al. Quantitative assessment of telomerase activity and human telomerase reverse transcriptase messenger RNA levels in pancreatic juice samples for the diagnosis of pancreatic cancer. Clin Cancer Res. 2005;11:2285–92.

    Article  PubMed  CAS  Google Scholar 

  34. Abrahamsen HN, Steiniche T, Nexo E, Hamilton-Dutoit SJ, Sorensen BS. Towards quantitative mRNA analysis in paraffin-embedded tissues using real-time reverse transcriptase-polymerase chain reaction: a methodological study on lymph nodes from melanoma patients. J Mol Diagn. 2003;5:34–41.

    Article  PubMed  CAS  Google Scholar 

  35. Antonov J, Goldstein DR, Oberli A, Baltzer A, Pirotta M, Fleischmann A, et al. Reliable gene expression measurements from degraded RNA by quantitative real-time PCR depend on short amplicons and a proper normalization. Lab Invest. 2005;85:1040–50.

    Article  PubMed  CAS  Google Scholar 

  36. Jung H, Jun KH, Jung JH, Chin HM, Park WB. The expression of Claudin-1, Claudin-2, Claudin-3, and Claudin-4 in gastric cancer tissue. J Surg Res. 2011;167:e185–91.

    Article  PubMed  CAS  Google Scholar 

  37. Hoffmann AC, Mori R, Vallbohmer D, Brabender J, Klein E, Drebber U, et al. High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia. 2008;10:674–9.

    PubMed  Google Scholar 

  38. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000;118:1001–11.

    Article  PubMed  CAS  Google Scholar 

  39. Martin TA, Mansel RE, Jiang WG. Antagonistic effect of NK4 on HGF/SF induced changes in the transendothelial resistance (TER) and paracellular permeability of human vascular endothelial cells. J Cell Physiol. 2002;192:268–75.

    Article  PubMed  CAS  Google Scholar 

  40. Ren J, Hamada J, Takeichi N, Fujikawa S, Kobayashi H. Ultrastructural differences in junctional intercellular communication between highly and weakly metastatic clones derived from rat mammary carcinoma. Cancer Res. 1990;50:358–62.

    PubMed  CAS  Google Scholar 

  41. Rajasekaran SA, Palmer LG, Quan K, Harper JF, Ball WJ Jr, Bander NH, et al. Na,K-ATPase beta-subunit is required for epithelial polarization, suppression of invasion, and cell motility. Mol Biol Cell. 2001;12:279–95.

    PubMed  CAS  Google Scholar 

  42. Hsueh C, Chang YS, Tseng NM, Liao CT, Hsueh S, Chang JH, et al. Expression pattern and prognostic significance of claudins 1, 4, and 7 in nasopharyngeal carcinoma. Hum Pathol. 2010;41:944–50.

    Article  PubMed  CAS  Google Scholar 

  43. Ohtani S, Terashima M, Satoh J, Soeta N, Saze Z, Kashimura S, et al. Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival. Gastric Cancer. 2009;12:43–51.

    Article  PubMed  CAS  Google Scholar 

  44. Michl P, Buchholz M, Rolke M, Kunsch S, Löhr M, McClane B, et al. Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology. 2001;121:678–84.

    Article  PubMed  CAS  Google Scholar 

  45. Suzuki M, Kato-Nakano M, Kawamoto S, Furuya A, Abe Y, Misaka H, et al. Therapeutic antitumor efficacy of monoclonal antibody against Claudin-4 for pancreatic and ovarian cancers. Cancer Sci. 2009;100:1623–30.

    Article  PubMed  CAS  Google Scholar 

  46. Kakutani H, Kondoh M, Saeki R, Fujii M, Watanabe Y, Mizuguchi H, et al. Claudin-4-targeting of diphtheria toxin fragment A using a C-terminal fragment of Clostridium perfringens enterotoxin. Eur J Pharm Biopharm. 2010;75:213–7.

    Article  PubMed  CAS  Google Scholar 

  47. Foss CA, Fox JJ, Feldmann G, Maitra A, Iacobuzio-Donohue C, Kern SE, et al. Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen: initial imaging in experimental models of pancreatic cancer. Mol Imaging. 2007;6:131–9.

    PubMed  Google Scholar 

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Acknowledgment

Supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kosuke Tsutsumi MD, PhD, Norihiro Sato MD, PhD, Reiko Tanabe MD, Kazuhiro Mizumoto MD, PhD, Tadashi Kayashima MD, Hayato Fujita MD, PhD, Kenoki Ohuchida MD, PhD, Takao Ohtsuka MD, PhD, Shunichi Takahata MD, PhD, Masafumi Nakamura MD, PhD & Masao Tanaka MD, PhD, FACS

  2. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Katsuya Morimatsu MD

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  1. Kosuke Tsutsumi MD, PhD
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  2. Norihiro Sato MD, PhD
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  3. Reiko Tanabe MD
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  4. Kazuhiro Mizumoto MD, PhD
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  12. Masao Tanaka MD, PhD, FACS
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Correspondence to Norihiro Sato MD, PhD.

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Tsutsumi, K., Sato, N., Tanabe, R. et al. Claudin-4 Expression Predicts Survival in Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 19 (Suppl 3), 491–499 (2012). https://doi.org/10.1245/s10434-011-1970-2

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  • DOI: https://doi.org/10.1245/s10434-011-1970-2

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