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Published in: Surgery Today 6/2015

01-06-2015 | Original Article

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

Authors: Kosuke Oishi, Takanori Sakaguchi, Satoshi Baba, Shohachi Suzuki, Hiroyuki Konno

Published in: Surgery Today | Issue 6/2015

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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.
Literature
1.
go back to reference The Liver Cancer Group of Japan. Primary liver cancer in Japan. Ann Surg. 1990;211:277–87. The Liver Cancer Group of Japan. Primary liver cancer in Japan. Ann Surg. 1990;211:277–87.
2.
go back to reference 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.CrossRef 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.CrossRef
3.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
4.
go back to reference Gatto M, Alvaro D. Cholangiocarcinoma: risk factors and clinical presentation. Eur Rev Med Pharmacol Sci. 2010;14:363–7.PubMed Gatto M, Alvaro D. Cholangiocarcinoma: risk factors and clinical presentation. Eur Rev Med Pharmacol Sci. 2010;14:363–7.PubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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 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
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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 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
11.
go back to reference Bij GJ, Bogels M, Oosterling SJ, et al. Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases. Cancer Lett. 2008;262:77–86.CrossRefPubMed Bij GJ, Bogels M, Oosterling SJ, et al. Tumor infiltrating macrophages reduce development of peritoneal colorectal carcinoma metastases. Cancer Lett. 2008;262:77–86.CrossRefPubMed
12.
go back to reference Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12.CrossRefPubMed Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
22.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
23.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edn. New Jersey: John Wiley & Sons; 2002. pp. 114–117. Sobin LH, Wittekind C. TNM classification of malignant tumours, 6th edn. New Jersey: John Wiley & Sons; 2002. pp. 114–117.
26.
go back to reference Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumor progression. Semin Cancer Biol. 2008;18:349–55.CrossRefPubMed Sica A, Larghi P, Mancino A, et al. Macrophage polarization in tumor progression. Semin Cancer Biol. 2008;18:349–55.CrossRefPubMed
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
29.
go back to reference Fiona J, Pixley E, Stanley R. CSF-1 regulation of the wandering macrophage: complexity in action. Trend Cell Biol. 2004;14:628–38.CrossRef Fiona J, Pixley E, Stanley R. CSF-1 regulation of the wandering macrophage: complexity in action. Trend Cell Biol. 2004;14:628–38.CrossRef
30.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
31.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
32.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
34.
go back to reference 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.CrossRef 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.CrossRef
35.
go back to reference 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.CrossRef 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.CrossRef
36.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
37.
go back to reference 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.CrossRefPubMedCentralPubMed 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.CrossRefPubMedCentralPubMed
Metadata
Title
Macrophage density and macrophage colony-stimulating factor expression predict the postoperative prognosis in patients with intrahepatic cholangiocarcinoma
Authors
Kosuke Oishi
Takanori Sakaguchi
Satoshi Baba
Shohachi Suzuki
Hiroyuki Konno
Publication date
01-06-2015
Publisher
Springer Japan
Published in
Surgery Today / Issue 6/2015
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-014-0989-y

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