Skip to main content

Postoperative Prognostic Predictors of Pancreatic Ductal Adenocarcinoma: Clinical Analysis and Immunoprofile on Tissue Microarrays

Annals of Surgical Oncology volume 19, pages 2664–2672 (2012)Cite this article

Abstract

Background

Most pancreatic ductal adenocarcinomas (PDACs) metastasize even after curative resection. Our goal was to investigate the important factors affecting metastasis and overall survival (OS).

Methods

We studied 88 PDACs with R0 resection and evaluated immunohistochemical markers on tissue microarrays to assess the expression levels of the following: EGFR, amphiregulin, VEGF, p-c-met, MMP2, MMP7, MMP9, CXCR3, and CXCR4.

Results

The median OS in patients who had positive versus negative expression of AREG and MMP9 were 25 versus 16 months and 24 versus 13 months, respectively (P = 0.03, P = 0.006). However, the median OS in patients with positive versus negative expression of MMP2 was 22 versus 37 months (P = 0.04). Immunoprofiles also revealed that patients with positive expression of p-c-met or VEGF had significantly shorter distant metastasis-free survival. Adjuvant treatment, postoperative decrease of CA 19-9, angiolymphatic invasion, AREG, and MMP2 were independent prognostic factors affecting OS in multivariate analysis.

Conclusions

Immunoprofiles revealed the groups with unfavorable tumor biology: negative expression of AREG and positive expression of MMP2. Also, high immunoreactivity of p-c-met or VEGF seemed to be associated with early distant organ metastasis in R0 resected PDACs; however, they still need to be further investigated. These results may give us useful insights in understanding the tumor biology and the patterns of PDAC dissemination.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.

    PubMed  Article  Google Scholar 

  2. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg. 1997;226:248–57.

    PubMed  Article  CAS  Google Scholar 

  3. Real FX. A “catastrophic hypothesis” for pancreas cancer progression. Gastroenterology. 2003;124:1958–64.

    PubMed  Article  Google Scholar 

  4. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.

    PubMed  Article  CAS  Google Scholar 

  5. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer. 2004;4:448–56.

    PubMed  Article  CAS  Google Scholar 

  6. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.

    PubMed  Article  CAS  Google Scholar 

  7. Christofori G. New signals from the invasive front. Nature. 2006;441(7092):444–50.

    PubMed  Article  CAS  Google Scholar 

  8. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.

    PubMed  Article  CAS  Google Scholar 

  9. Shoyab M, McDonald VL, Bradley JG, et al. Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proc Natl Acad Sci USA. 1988;85:6528–32.

    PubMed  Article  CAS  Google Scholar 

  10. Shoyab M, Plowman GD, McDonald VL, et al. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science. 1989;243(4894 Pt 1):1074–6.

    PubMed  Article  CAS  Google Scholar 

  11. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    PubMed  Article  CAS  Google Scholar 

  12. Yotsumoto F, Yagi H, Suzuki SO, et al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun. 2008;365:555–61.

    PubMed  Article  CAS  Google Scholar 

  13. Yamada M, Ichikawa Y, Yamagishi S, et al. Amphiregulin is a promising prognostic marker for liver metastases of colorectal cancer. Clin Cancer Res. 2008;14:2351–6.

    PubMed  Article  CAS  Google Scholar 

  14. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.

    PubMed  Article  CAS  Google Scholar 

  15. Freije JM, Balbin M, Pendas AM, et al. Matrix metalloproteinases and tumor progression. Adv Exp Med Biol. 2003;532:91–107.

    PubMed  Article  CAS  Google Scholar 

  16. Lopez-Otin C, Matrisian LM. Emerging roles of proteases in tumour suppression. Nat Rev Cancer. 2007;7:800–8.

    PubMed  Article  CAS  Google Scholar 

  17. Bramhall SR, Neoptolemos JP, Stamp GW, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol. 1997;182:347–55.

    PubMed  Article  CAS  Google Scholar 

  18. Gress TM, Muller-Pillasch F, Lerch MM, et al. Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer. 1995;62:407–13.

    PubMed  Article  CAS  Google Scholar 

  19. Scorilas A, Karameris A, Arnogiannaki N, et al. Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer. 2001;84:1488–96.

    PubMed  Article  CAS  Google Scholar 

  20. Takeha S, Fujiyama Y, Bamba T, et al. Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect. Jpn J Cancer Res. 1997;88:72–81.

    PubMed  Article  CAS  Google Scholar 

  21. Pozzi A, LeVine WF, Gardner HA. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene. 2002;21:272–81.

    PubMed  Article  CAS  Google Scholar 

  22. Hamano Y, Zeisberg M, Sugimoto H, et al. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell. 2003;3:589–601.

    PubMed  Article  CAS  Google Scholar 

  23. Birkedal-Hansen H. Matrix metalloproteinases. Adv Dental Res. 1995;9(3 Suppl):16.

    Article  CAS  Google Scholar 

  24. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995;7:728–35.

    PubMed  Article  CAS  Google Scholar 

  25. Juuti A, Lundin J, Nordling S, et al. Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer. Oncology. 2006;71:61–8.

    PubMed  Article  CAS  Google Scholar 

  26. Desruisseau S, Palmari J, Giusti C, et al. Clinical relevance of amphiregulin and VEGF in primary breast cancers. Int J Cancer. 2004;111:733–40.

    PubMed  Article  CAS  Google Scholar 

  27. Smith RA, Tang J, Tudur-Smith C, et al. Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer. 2011;104:1440–51.

    PubMed  Article  CAS  Google Scholar 

  28. Maulik G, Madhiwala P, Brooks S, et al. Activated c-Met signals through PI3 K with dramatic effects on cytoskeletal functions in small cell lung cancer. J Cell Mol Med. 2002;6:539–53.

    PubMed  Article  CAS  Google Scholar 

  29. Pisick E, Jagadeesh S, Salgia R. Receptor tyrosine kinases and inhibitors in lung cancer. Sci World J. 2004;4:589–604.

    Article  CAS  Google Scholar 

  30. Ide T, Kitajima Y, Miyoshi A, et al. The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol. 2007;14:2600–7.

    PubMed  Article  Google Scholar 

Download references

Acknowledgment

Supported in part by internal fund #800-20090061SNU in the Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Joo Kyung Park MD, Ji Kon Ryu MD, PhD, Yong Bum Yoon MD, PhD & Yong-Tae Kim MD, PhD

  2. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea

    Jin-Hyeok Hwang MD, PhD

  3. Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Min A. Kim MD, PhD & Gyeong Hoon Kang MD, PhD

  4. Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea

    Haeryoung Kim MD, PhD

  5. Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Sun-Whe Kim MD, PhD

  6. Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea

    Ho-Seong Han MD, PhD

Authors
  1. Joo Kyung Park MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min A. Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ji Kon Ryu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Bum Yoon MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sun-Whe Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ho-Seong Han MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gyeong Hoon Kang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haeryoung Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jin-Hyeok Hwang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yong-Tae Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin-Hyeok Hwang MD, PhD or Yong-Tae Kim MD, PhD.

Additional information

Joo Kyung Park and Min A. Kim contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 47 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Park, J.K., Kim, M.A., Ryu, J.K. et al. Postoperative Prognostic Predictors of Pancreatic Ductal Adenocarcinoma: Clinical Analysis and Immunoprofile on Tissue Microarrays. Ann Surg Oncol 19, 2664–2672 (2012). https://doi.org/10.1245/s10434-012-2277-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-012-2277-7

Keywords

  • Vascular Endothelial Growth Factor
  • Overall Survival
  • Epidermal Growth Factor Receptor
  • Pancreatic Ductal Adenocarcinoma
  • Carbohydrate Antigen