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Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma

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Abstract

Purpose

Nectin-1 is a cell adhesion molecule that regulates the formation of adherens junctions and tight junctions. We measured the expression of nectin-1 in cancer-associated fibroblasts (CAFs) in patients with pancreatic ductal adenocarcinoma (PDAC).

Methods

Nectin-1 expression was measured via immunohistochemistry using tissue microarray blocks constructed from resected PDAC tissue from 258 patients. We screened for associations between nectin-1 expression and clinicopathological parameters. According to the percentage of CAFs stained, expression was classified as negative at ≤ 30% and positive at > 30%.

Results

Nectin-1 expression was confirmed in CAFs from 64 patients (24.8%), and was associated with lymph node metastasis (p = 0.016), advanced Union for International Cancer Control stage (p = 0.016), perineural invasion (p = 0.022), pancreatic head tumors (p = 0.023), and shorter overall survival (p = 0.003). Multivariate analysis revealed that nectin-1 expression in CAFs was an independent prognostic factor (p = 0.038).

Conclusions

Diffuse nectin-1 expression in the CAFs of PDAC patients is associated with invasion, metastasis, and shorter survival.

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References

  1. Brentnall TA. Arousal of cancer-associated stromal fibroblasts: palladin-activated fibroblasts promote tumor invasion. Cell Adhes Migr. 2012;6:488–94.

    Article  Google Scholar 

  2. Pula B, Witkiewicz W, Dziegiel P, Podhorska-Okolow M. Significance of podoplanin expression in cancer-associated fibroblasts: a comprehensive review. Int J Oncol. 2013;42:1849–57.

    Article  CAS  PubMed  Google Scholar 

  3. Pula B, Wojnar A, Witkiewicz W, Dziegiel P, Podhorska-Okolow M. Podoplanin expression in cancer-associated fibroblasts correlates with VEGF-C expression in cancer cells of invasive ductal breast carcinoma. Neoplasma. 2013;60:516–24.

    Article  CAS  PubMed  Google Scholar 

  4. Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, et al. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008;123:1053–9.

    Article  CAS  PubMed  Google Scholar 

  5. Lai D, Ma L, Wang F. Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells. Int J Oncol. 2012;41:541–50.

    Article  CAS  PubMed  Google Scholar 

  6. Garcia-Pravia C, Galvan JA, Gutierrez-Corral N, Solar-García L, García-Pérez E, García-Ocaña M, et al. Overexpression of COL11A1 by cancer-associated fibroblasts: clinical relevance of a stromal marker in pancreatic cancer. PloS One. 2013;8:e78327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Brentnall TA, Lai LA, Coleman J, Bronner MP, Pan S, Chen R. Arousal of cancer-associated stroma: overexpression of palladin activates fibroblasts to promote tumor invasion. PloS One. 2012;7:e30219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Goicoechea SM, Garcia-Mata R, Staub J, Valdivia A, Sharek L, McCulloch CG, et al. Palladin promotes invasion of pancreatic cancer cells by enhancing invadopodia formation in cancer-associated fibroblasts. Oncogene. 2014;33:1265–73.

    Article  CAS  PubMed  Google Scholar 

  9. Ino Y, Yamazaki-Itoh R, Oguro S, Shimada K, Kosuge T, Zavada J, et al. Arginase II expressed in cancer-associated fibroblasts indicates tissue hypoxia and predicts poor outcome in patients with pancreatic cancer. PloS One. 2013;8:e55146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Okada K, Hirabayashi K, Imaizumi T, Matsuyama M, Yazawa N, Dowaki S, et al. Stromal thrombospondin-1 expression is a prognostic indicator and a new marker of invasiveness in intraductal papillary-mucinous neoplasm of the pancreas. Biomed Res. 2010;31:13–9.

    Article  CAS  PubMed  Google Scholar 

  11. Tobita K, Kijima H, Dowaki S, Oida Y, Kashiwagi H, Ishii M, et al. Thrombospondin-1 expression as a prognostic predictor of pancreatic ductal carcinoma. Int J Oncol. 2002;21:1189–95.

    CAS  PubMed  Google Scholar 

  12. 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;25:719–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shindo K, Aishima S, Ohuchida K, Fujiwara K, Fujino M, Mizuuchi Y, et al. Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol Cancer. 2013;12:168.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Walter K, Omura N, Hong SM, Griffith M, Vincent A, Borges M, et al. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin Cancer Res. 2010;16:1781–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Takai Y, Miyoshi J, Ikeda W, Ogita H. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol. 2008;9:603–15.

    Article  CAS  PubMed  Google Scholar 

  16. Takai Y, Irie K, Shimizu K, Sakisaka T, Ikeda W. Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization. Cancer Sci. 2003;94:655–67.

    Article  CAS  PubMed  Google Scholar 

  17. Takai Y, Nakanishi H. Nectin and afadin: novel organizers of intercellular junctions. J Cell Sci. 2003;116:17–27.

    Article  CAS  PubMed  Google Scholar 

  18. Guzman G, Oh S, Shukla D, Valyi-Nagy T. Nectin-1 expression in the normal and neoplastic human uterine cervix. Arch Pathol Lab Med. 2006;130:1193–5.

    CAS  PubMed  Google Scholar 

  19. Izumi H, Hirabayashi K, Nakamura N, Nakagohri T. Nectin expression in pancreatic adenocarcinoma: nectin-3 is associated with a poor prognosis. Surg Today. 2015;45:487–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brierley J, Gospodarowicz M, Wittekind C. UICC TNM Classification of Malignant Tumours. 8th ed. Hoboken (New Jersey): Wiley Blackwell; 2017.

    Google Scholar 

  21. Kawanishi A, Hirabayashi K, Yamada M, Takanashi Y, Hadano A, Kawaguchi Y, et al. Clinicopathological significance of Necl-4 expression in pancreatic ductal adenocarcinoma. J Clin Pathol. 2017;70:619–24.

    Article  PubMed  Google Scholar 

  22. Matsushima H, Utani A, Endo H, Matsuura H, Kakuta M, Nakamura Y, et al. The expression of nectin-1alpha in normal human skin and various skin tumours. Br J Dermatol. 2003;148:755–62.

    Article  CAS  PubMed  Google Scholar 

  23. Hazan RB, Kang L, Whooley BP, Borgen PI. N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes Commun. 1997;4:399–411.

    Article  CAS  PubMed  Google Scholar 

  24. Tran NL, Nagle RB, Cress AE, Heimark RL. N-Cadherin expression in human prostate carcinoma cell lines. An epithelial–mesenchymal transformation mediating adhesion with stromal cells. Am J Pathol. 1999;155:787–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Roberts DD. Regulation of tumor growth and metastasis by thrombospondin-1. FASEB J. 1996;10:1183–91.

    Article  CAS  PubMed  Google Scholar 

  26. Dong L, Ge XY, Wang YX, Yang LQ, Li SL, Yu GY, et al. Transforming growth factor-beta and epithelial–mesenchymal transition are associated with pulmonary metastasis in adenoid cystic carcinoma. Oral Oncol. 2013;49:1051–8.

    Article  CAS  PubMed  Google Scholar 

  27. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.

    Article  CAS  PubMed  Google Scholar 

  28. Sun XD, Liu XE, Huang DS. Curcumin reverses the epithelial–mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol Rep. 2013;29:2401–7.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou B, Chen WL, Wang YY, Lin ZY, Zhang DM, Fan S, et al. A role for cancer-associated fibroblasts in inducing the epithelial-to-mesenchymal transition in human tongue squamous cell carcinoma. J Oral Pathol Med. 2014;43:585–92.

    Article  CAS  PubMed  Google Scholar 

  30. Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ, Feng YM. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer. 2014;110:724–32.

    Article  CAS  PubMed  Google Scholar 

  31. Bronsert P, Kohler I, Timme S, Kiefer S, Werner M, Schilling O, et al. Prognostic significance of Zinc finger E-box binding homeobox 1 (ZEB1) expression in cancer cells and cancer-associated fibroblasts in pancreatic head cancer. Surgery. 2014;156:97–108.

    Article  PubMed  Google Scholar 

  32. Bojesen KB, Clausen O, Rohde K, Christensen C, Zhang L, Li S, et al. Nectin-1 binds and signals through the fibroblast growth factor receptor. J Biol Chem. 2012;287:37420–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29.

    Article  CAS  PubMed  Google Scholar 

  34. Nomura S, Yoshitomi H, Takano S, Shida T, Kobayashi S, Ohtsuka M, et al. FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer. Br J Cancer. 2008;99:305–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Artinyan A, Soriano PA, Prendergast C, Low T, Ellenhorn JD, Kim J. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB (Oxford). 2008;10:371–6.

    Article  Google Scholar 

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Acknowledgements

We thank the Division of Diagnostic Pathology, Tokai University Hospital, and the Support Center for Medical Research and Education, Tokai University for their valuable technical assistance.

Funding

This study was supported by the Research and Study Project of the Tokai University Educational System’s General Research Organization, the Pancreas Research Foundation of Japan, and a Grant-in-Aid for Scientific Research (C) (16K08659).

Author information

Authors and Affiliations

  1. Department of Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Kanagawa, Japan

    Misuzu Yamada, Hideki Izumi & Toshio Nakagohri

  2. Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Kenichi Hirabayashi, Yumi Takanashi & Naoya Nakamura

  3. Department of Gastroenterology and Hepatology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Kanagawa, Japan

    Aya Kawanishi, Atsuko Hadano, Yoshiaki Kawaguchi & Tetsuya Mine

Authors
  1. Misuzu Yamada
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  2. Kenichi Hirabayashi
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  3. Aya Kawanishi
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  4. Atsuko Hadano
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  5. Yumi Takanashi
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  6. Hideki Izumi
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  7. Yoshiaki Kawaguchi
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  8. Tetsuya Mine
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  9. Naoya Nakamura
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  10. Toshio Nakagohri
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Corresponding author

Correspondence to Kenichi Hirabayashi.

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Ethics approval

The study protocol was approved by the Research Ethics Committee (no. 13R244) of the Tokai University School of Medicine (Kanagawa, Japan) and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Conflict of interest

We declare that we have no conflicts of interest.

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Yamada, M., Hirabayashi, K., Kawanishi, A. et al. Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma. Surg Today 48, 510–516 (2018). https://doi.org/10.1007/s00595-017-1618-3

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  • DOI: https://doi.org/10.1007/s00595-017-1618-3

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