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Annals of Surgical Oncology

, Volume 19, Issue 7, pp 2264–2271 | Cite as

Clinical Significance of Folate Receptor β–expressing Tumor-associated Macrophages in Pancreatic Cancer

  • Hiroshi Kurahara
  • Sonshin TakaoEmail author
  • Taisaku Kuwahata
  • Taku Nagai
  • Qiang Ding
  • Koki Maeda
  • Hiroyuki Shinchi
  • Yuko Mataki
  • Kosei Maemura
  • Takami Matsuyama
  • Shoji Natsugoe
Pancreatic Tumors

Abstract

Purpose

To examine the appearance and distribution of folate receptor β-expressing (FRβ+) macrophages in the pancreatic tumor microenvironment and their relationship to metastasis and prognosis in pancreatic cancer patients.

Methods

Tumor samples were obtained from 76 patients with pancreatic cancer who underwent curative resection. None of these patients had received any preoperative chemotherapy or radiotherapy. Both FRβ+ and tumor-infiltrating (CD68+) macrophages were examined in each tumor specimen by immunohistochemical and immunofluorescence staining using a newly developed anti-human FRβ monoclonal antibody and CD68 antibody. The appearance, distribution, expression of vascular endothelial growth factor (VEGF) on FRβ-expressing or CD68+ macrophages, and tumor microvessel density (MVD) were assessed. Log rank test and Cox proportional hazard regression were used to investigate the associations among CD68+ or FRβ+ macrophages, clinicopathologic factors, and overall survival.

Results

FRβ+ macrophages were prominent in the perivascular regions of the tumor-invasive front and a specific subset with VEGF expression in the CD68+ macrophages. A high number of FRβ+ macrophages showed a positive association with high MVD, a high incidence of hematogenous metastasis, and a poor prognosis in pancreatic cancer patients.

Conclusions

FRβ+ macrophages are a novel subset of tumor-associated macrophages in pancreatic cancer and may play an important role in the tumor microenvironment in association with systemic metastasis through the interaction with tumor cells and vessels. FRβ+ macrophages may be promising a targeting therapy for pancreatic cancer.

Keywords

Vascular Endothelial Growth Factor Pancreatic Cancer Tumor Microenvironment Vascular Endothelial Growth Factor Expression Pancreatic Cancer Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

Supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Ministry of Health, Labour, and Welfare, Japan.

References

  1. 1.
    Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7:163–72.PubMedCrossRefGoogle Scholar
  2. 2.
    Liotta LA, Kohn EC. The microenvironment of the tumour–host interface. Nature. 2001;411:375–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet. 2008;371:771–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007;67:5064–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Tsuzuki Y, Mouta Carreira C, Bockhorn M, Xu L, Jain RK, Fukumura D. Pancreas microenvironment promotes VEGF expression and tumor growth: novel window models for pancreatic tumor angiogenesis and microcirculation. Lab Invest. 2001;81:1439–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Takao S, Takebayashi Y, Che X, et al. Expression of thymidine phosphorylase is associated with a poor prognosis in patients with ductal adenocarcinoma of the pancreas. Clin Cancer Res. 1998;4:1619–24.PubMedGoogle Scholar
  9. 9.
    Karademir S, Sökmen S, Terzi C, et al. Tumor angiogenesis as a prognostic predictor in pancreatic cancer. J Hepatobiliary Pancreat Surg. 2000;7:489–95.PubMedCrossRefGoogle Scholar
  10. 10.
    Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A. The history of the angiogenic switch concept. Leukemia. 2007;21:44–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Esposito I, Menicagli M, Funel N, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol. 2004;57:630–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124:263–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66:605–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42:717–27.PubMedCrossRefGoogle Scholar
  16. 16.
    Bouhlel MA, Derudas B, Rigamonti E, et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007;6:137–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Lewis CE, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 2007;67:8429–32.PubMedCrossRefGoogle Scholar
  19. 19.
    Leamon CP, Jackman AL. Exploitation of the folate receptor in the management of cancer and inflammatory disease. Vitam Horm. 2008;79:203–33.PubMedCrossRefGoogle Scholar
  20. 20.
    Low PS, Kularatne SA. Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol. 2009;13:256–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Nagayoshi R, Nagai T, Matsushita K, et al. Effectiveness of anti-folate receptor beta antibody conjugated with truncated Pseudomonas exotoxin in the targeting of rheumatoid arthritis synovial macrophages. Arthritis Rheum. 2005;52:2666–75.PubMedCrossRefGoogle Scholar
  22. 22.
    Nagai T, Tanaka M, Tsuneyoshi Y, et al. Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta. Cancer Immunol Immunother. 2009;58:1577–86.PubMedCrossRefGoogle Scholar
  23. 23.
    Puig-Kröger A, Sierra-Filardi E, Dominguez-Soto A, et al. Folate receptor beta is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages. Cancer Res. 2009;69:9395–403.PubMedCrossRefGoogle Scholar
  24. 24.
    Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Kurahara H, Takao S, Maemura K, Shinchi H, Natsugoe S, Aikou T. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: its relationship to lymph node metastasis. Clin Cancer Res. 2004;10:8413–20.PubMedCrossRefGoogle Scholar
  26. 26.
    Sobin LH. International Union Against Cancer TNM classification of malignant tumours. 6th edition. New York: Wiley-Liss; 2002.Google Scholar
  27. 27.
    Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B. Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg. 2004;239:763–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Kurahara H, Shinchi H, Mataki Y, et al. Significance of M2-polarized tumor associated macrophage in pancreatic cancer. J Surg Res. 2011;167:e211–9.PubMedCrossRefGoogle Scholar
  30. 30.
    De Palma M, Naldini L. Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis. Biochim Biophys Acta. 2006;1766:159–66.PubMedGoogle Scholar
  31. 31.
    Robinson BD, Sica GL, Liu YF, et al. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res. 2009;15:2433–41.PubMedCrossRefGoogle Scholar
  32. 32.
    De Palma M, Venneri MA, Galli R, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211–26.PubMedCrossRefGoogle Scholar
  33. 33.
    Murdoch C, Tazzyman S, Webster S, Lewis CE. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol. 2007;178:7405–11.PubMedGoogle Scholar
  34. 34.
    Coffelt SB, Tal AO, Scholz A, et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res. 2010;70:5270–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Venneri MA, De Palma M, Ponzoni M, et al. Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood. 2007;109:5276–85.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Hiroshi Kurahara
    • 1
  • Sonshin Takao
    • 2
    • 3
    Email author
  • Taisaku Kuwahata
    • 1
    • 3
  • Taku Nagai
    • 4
  • Qiang Ding
    • 3
  • Koki Maeda
    • 1
    • 3
  • Hiroyuki Shinchi
    • 5
  • Yuko Mataki
    • 1
  • Kosei Maemura
    • 1
  • Takami Matsuyama
    • 4
  • Shoji Natsugoe
    • 1
  1. 1.Department of Digestive SurgeryKagoshima UniversityKagoshimaJapan
  2. 2.Department of Cancer and Regenerative MedicineKagoshima UniversityKagoshimaJapan
  3. 3.Frontier Science Research CenterKagoshima UniversityKagoshimaJapan
  4. 4.Department of ImmunologyGraduate School of Medical Sciences, Kagoshima UniversityKagoshimaJapan
  5. 5.Department of Health SciencesKagoshima UniversityKagoshimaJapan

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