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Macrophage density and macrophage colony-stimulating factor expression predict the postoperative prognosis in patients with intrahepatic cholangiocarcinoma

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Abstract

Purposes

Macrophages are included in the stromal compartments in various neoplasms, and their behavior against tumors is diverse. The aim of this study was to examine the role of tumor-infiltrating macrophages and their main regulator, macrophage colony-stimulating factor (M-CSF), in intrahepatic cholangiocarcinoma (ICC).

Methods

Macrophage density and M-CSF expression in 39 resected ICC specimens were immunohistochemically evaluated in the central and peripheral areas of tumors, which were defined as fields more than and within 500 μm from the invasive front, respectively. The number of CD68-positive macrophages was counted using an image-analyzing software program. The relationship between these results and other clinicopathological factors and the postoperative prognosis were evaluated.

Results

Sporadic M-CSF expression in cancer cells around the peripheral area was observed in fourteen patients. M-CSF-positive ICCs showed a higher macrophage density in the tumor-peripheral area than did M-CSF-negative ICCs. M-CSF expression and higher macrophage density in the tumor-peripheral area were related to a better postoperative prognosis, whereas a higher macrophage density in the central area was one of the significant risk factors for a poor prognosis in a univariate analysis.

Conclusion

Tumor-peripheral macrophage infiltration, presumably dependent on M-CSF, and M-CSF-independent tumor-central macrophage infiltration are predictive factors for better and worse postoperative prognosis in ICC patients, respectively. The tumor microenvironment, such as the presence of hypoxia, may affect the behavior of infiltrating macrophages in ICC.

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Abbreviations

ICC:

Intrahepatic cholangiocarcinoma

TAM:

Tumor-associated macrophage

M-CSF:

Macrophage colony-stimulating factor

HIF:

Hypoxia-inducible factor

VEGF:

Vascular endothelial growth factor

HCC:

Hepatocellular carcinoma

References

  1. The Liver Cancer Group of Japan. Primary liver cancer in Japan. Ann Surg. 1990;211:277–87.

    Google Scholar 

  2. Ikai I, Okazaki M, Okita L, et al. Report of the 17th Nationwide follow-up survey of primary liver cancer in Japan. Hepatol Res. 2007;39:676–91.

    Article  Google Scholar 

  3. Welzel TM, Graubard BI, El-Serag HB. Risk factors for intra- and extrahepatic cholangiocarcinoma in the United States: a population based case-control study. Clin Gastroenterol Hepatol. 2007;5:1221–8.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Gatto M, Alvaro D. Cholangiocarcinoma: risk factors and clinical presentation. Eur Rev Med Pharmacol Sci. 2010;14:363–7.

    CAS  PubMed  Google Scholar 

  5. Hasita H, Komohara Y, Okabe H, et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010;101(8):1913–9.

    Article  CAS  PubMed  Google Scholar 

  6. Ding T, Xu J, Wang F, et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol. 2009;40:381–9.

    Article  CAS  PubMed  Google Scholar 

  7. Li YW, Qiu SJ, Fan J, et al. Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection. J Cancer Res Clin Oncol. 2009;135(3):439–49.

    Article  PubMed  Google Scholar 

  8. Ohno S, Hiroyuki I, Dhar DJ, et al. The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival gastric cancer patients. Anticancer Res. 2003;23:5015–22.

    PubMed  Google Scholar 

  9. Forssell J, Oberg A, Henriksson ML. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13(5):1472–9.

    Article  CAS  PubMed  Google Scholar 

  10. Ohno S, Ohno Y, Suzuki N, et al. Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res. 2004;24:3335–42.

    PubMed  Google Scholar 

  11. Bij GJ, Bogels M, Oosterling SJ, et al. Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases. Cancer Lett. 2008;262:77–86.

    Article  PubMed  Google Scholar 

  12. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12.

    Article  CAS  PubMed  Google Scholar 

  13. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.

    Article  CAS  PubMed  Google Scholar 

  14. Ma J, Liu L, Che G, et al. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer. 2010;10:112.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Komohara Y, Ohnishi K, Kuratsu J, et al. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216:15–24.

    Article  CAS  PubMed  Google Scholar 

  16. Niino D, Komohara Y, Murayama T, et al. Ratio of M2 macrophage expression is closely associated with poor prognosis for Angioimmunoblastic T-cell lymphoma (AITL). Pathol Int. 2010;60:278–83.

    Article  PubMed  Google Scholar 

  17. Laoui D, Movahedi K, Overmeire EV, et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol. 2011;55:861–7.

    Article  PubMed  Google Scholar 

  18. Zhang B, Yac G, Zhang Y, et al. M2-Polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics. 2011;66:1879–86.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Zhu XD, Zhang JB, Zhuang PY, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26(16):2707–16.

    Article  PubMed  Google Scholar 

  20. Toy EP, Chambers JT, Kaminski BM, et al. The activated macrophage colony-stimulating factor (CSF-1) receptor as a predictor of poor outcome in advanced epithelial ovarian carcinoma. Gynecol Oncol. 2001;80:194–200.

    Article  CAS  PubMed  Google Scholar 

  21. Beck AH, Espinosa I, Edris B, et al. The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res. 2009;15:778–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Corzo CA, Condamine T, Lu L, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Takeda N, O’Dea EL, Doedens A, et al. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24:491–501.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Mason RP, Antich PP, Babcock EE, et al. Non-invasive determination of tumor oxygen tension and local variation with growth. Int J Radiat Oncol Biol Phys. 1994;29:95–103.

    Article  CAS  PubMed  Google Scholar 

  25. Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edn. New Jersey: John Wiley & Sons; 2002. pp. 114–117.

  26. Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumor progression. Semin Cancer Biol. 2008;18:349–55.

    Article  CAS  PubMed  Google Scholar 

  27. Aharinejad S, Paulus P, Sioud M, et al. Colony stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res. 2004;64:5378–84.

    Article  CAS  PubMed  Google Scholar 

  28. Mroczko B, Groblewska M, Wereszczynska-Siemiatkowska U, et al. Serum macrophage-colony stimulating factor levels in colorectal cancer patient correlate with lymph node metastasis and prognosis. Clin Chim Acta. 2007;380:208–12.

    Article  CAS  PubMed  Google Scholar 

  29. Fiona J, Pixley E, Stanley R. CSF-1 regulation of the wandering macrophage: complexity in action. Trend Cell Biol. 2004;14:628–38.

    Article  Google Scholar 

  30. Eubank TD, Roberts RD, Khan M, et al. Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. Cancer Res. 2009;69:2133–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Menke J, Kriegsmann J, Schimanski CS, et al. Autocrine CSF-1 and CSF-1 receptor coexpression promotes renal cell carcinoma growth. Cancer Res. 2012;72:187–200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Fujii H, Sakata K, Katsumata Y, et al. Tissue oxygenation in a murine SCC VII tumor after X-ray irradiation as determined by EPR spectroscopy. Radiother Oncol. 2008;86:354–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Wu WK, Llewellyn OP, Bates DO, et al. IL-10 regulation of macrophage VEGF production is dependent on macrophage polarization and hypoxia. Immunobiology. 2010;215:796–803.

    Article  CAS  PubMed  Google Scholar 

  34. Murdoch C, Giannoudis A, Lewis CE, et al. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;15(8):2224–34.

    Article  Google Scholar 

  35. Elbarghatia L, Murdochb C, Lewis CE, et al. Effects of hypoxia on transcription factor expression in human monocytes and macrophages. Immunobiology. 2008;213:899–908.

    Article  Google Scholar 

  36. Fang HY, Hughes R, Murdoch C, et al. Hypoxia-inducible factor 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood. 2009;114:844–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Imtiyaz HZ, Williams EP, Hickey MM, et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120:2699–714.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the participating laboratory technicians in the Department of Pathology, Hamamatsu University Hospital, for their support and technical skills.

Conflict of interest

Kosuke Oishi and co-authors have no conflicts of interest.

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Authors and Affiliations

  1. Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Kosuke Oishi, Takanori Sakaguchi & Hiroyuki Konno

  2. Faculty of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Satoshi Baba

  3. Department of Surgery, Iwata City Hospital, 512-3 Okubo, Iwata, 438-8550, Japan

    Shohachi Suzuki

  4. Kikugawa City Hospital, 1632 Higashiyokochi, Kikugawa, 439-0022, Japan

    Kosuke Oishi

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  1. Kosuke Oishi
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  2. Takanori Sakaguchi
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  3. Satoshi Baba
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  4. Shohachi Suzuki
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  5. Hiroyuki Konno
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Correspondence to Kosuke Oishi.

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Oishi, K., Sakaguchi, T., Baba, S. et al. Macrophage density and macrophage colony-stimulating factor expression predict the postoperative prognosis in patients with intrahepatic cholangiocarcinoma. Surg Today 45, 715–722 (2015). https://doi.org/10.1007/s00595-014-0989-y

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  • DOI: https://doi.org/10.1007/s00595-014-0989-y

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