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01-02-2014 | Original Article

Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma

Authors: Carl Ludwig Behnes, Felix Bremmer, Bernhard Hemmerlein, Arne Strauss, Philipp Ströbel, Heinz-Joachim Radzun

Published in: Virchows Archiv | Issue 2/2014

Abstract

Tumor-associated macrophages (TAMs) play a key role in cancer development. Especially, the immunosuppressive M2 phenotype is associated with increased tumor growth, invasiveness and metastasis. The differentiation of macrophages to the alternative phenotype M2 is mediated, inter alia, by macrophage colony-stimulating factor (M-CSF). Papillary renal cell carcinoma (RCC) represents a rare tumor type which, based upon histological criteria, can be subdivided into two subtypes (I and II), of which type II is associated with poor prognosis. In both subtypes, typically, a dense infiltrate of macrophages is found. In the present study, the expression of CD68, CD163, M-CSF, Ki-67, and CD31 was examined in 30 type I and 30 type II papillary RCCs (n = 60). Both types of papillary RCCs contained an equally dense infiltrate of CD68-positive macrophages. Nearly all macrophages in papillary RCC type II expressed CD163, a characteristic for M2 macrophages. In type I papillary RCC, less than 30 % of macrophages expressed CD163. Furthermore, tumor cells in type II papillary RCC expressed significantly more M-CSF and showed increased (Ki-67 expression defined) proliferative activity in comparison with type I papillary RCC. In addition, the (CD31 defined) capillary density was higher in type II than in type I papillary RCC. A dense infiltrate of M2 phenotype TAM and high M-CSF expression in tumor cells are key features of type II papillary RCC. These findings might explain why the prognosis of papillary RCC type II is worse than that of type I.

Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545. doi:10.1016/S0140-6736(00)04046-0 PubMedCrossRef

Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205 PubMedCrossRef

Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35. doi:10.1038/nri978 PubMedCrossRef

Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555PubMedCrossRef

Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25(12):677–686. doi:10.1016/j.it.2004.09.015 PubMedCrossRef

Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73(2):209–212PubMedCrossRef

Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. doi:10.1016/j.cell.2010.03.014 PubMedCrossRef

Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124(2):263–266. doi:10.1016/j.cell.2006.01.007 PubMedCrossRef

Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237. doi:10.1016/j.coi.2010.01.009 PubMedCrossRef

10.

Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78. doi:10.1038/nrc1256 PubMedCrossRef

11.

Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, Takeya M (2011) Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 102(7):1424–1431. doi:10.1111/j.1349-7006.2011.01945.x PubMedCrossRef

12.

Mydlo JH, Bard RH (1987) Analysis of papillary renal adenocarcinoma. Urology 30(6):529–534PubMedCrossRef

13.

Delahunt B, Eble JN (1997) Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10(6):537–544PubMed

14.

Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ (2000) Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer 89(3):604–614PubMedCrossRef

15.

Pignot G, Elie C, Conquy S, Vieillefond A, Flam T, Zerbib M, Debre B, Amsellem-Ouazana D (2007) Survival analysis of 130 patients with papillary renal cell carcinoma: prognostic utility of type 1 and type 2 subclassification. Urology 69(2):230–235. doi:10.1016/j.urology.2006.09.052 PubMedCrossRef

16.

Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86(5):1065–1073. doi:10.1189/jlb.0609385 PubMedCrossRef

17.

Webster WS, Lohse CM, Thompson RH, Dong H, Frigola X, Dicks DL, Sengupta S, Frank I, Leibovich BC, Blute ML, Cheville JC, Kwon ED (2006) Mononuclear cell infiltration in clear-cell renal cell carcinoma independently predicts patient survival. Cancer 107(1):46–53. doi:10.1002/cncr.21951 PubMedCrossRef

18.

Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56(20):4625–4629PubMed

19.

Shabo I, Stal O, Olsson H, Dore S, Svanvik J (2008) Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer 123(4):780–786. doi:10.1002/ijc.23527 PubMedCrossRef

20.

Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N, Kato Y, Aizawa M, Ochiai A (2012) Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci 103(11):2012–2020. doi:10.1111/j.1349-7006.2012.02411.x PubMedCrossRef

21.

Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022–7029. doi:10.1158/0008-5472.CAN-04-1449 PubMedCrossRef

22.

Kacinski BM (1995) CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann Med 27(1):79–85PubMedCrossRef

23.

Smith HO, Anderson PS, Kuo DY, Goldberg GL, DeVictoria CL, Boocock CA, Jones JG, Runowicz CD, Stanley ER, Pollard JW (1995) The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma. Clin Cancer Res 1(3):313–325PubMed

24.

Scholl SM, Pallud C, Beuvon F, Hacene K, Stanley ER, Rohrschneider L, Tang R, Pouillart P, Lidereau R (1994) Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. J Natl Cancer Inst 86(2):120–126PubMedCrossRef

25.

Nowicki A, Szenajch J, Ostrowska G, Wojtowicz A, Wojtowicz K, Kruszewski AA, Maruszynski M, Aukerman SL, Wiktor-Jedrzejczak W (1996) Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer J Int cancer 65(1):112–119. doi:10.1002/(SICI)1097-0215(19960103)65:1<112::AID-IJC19>3.0.CO;2-I CrossRef

26.

Kawamura K, Komohara Y, Takaishi K, Katabuchi H, Takeya M (2009) Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors. Pathol Int 59(5):300–305. doi:10.1111/j.1440-1827.2009.02369.x PubMedCrossRef

27.

O’Sullivan C, Lewis CE, Harris AL, McGee JO (1993) Secretion of epidermal growth factor by macrophages associated with breast carcinoma. Lancet 342(8864):148–149PubMedCrossRef

28.

Murray PJ (2007) The JAK-STAT signaling pathway: input and output integration. J Immunol 178(5):2623–2629PubMedCrossRef

29.

Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727. doi:10.1016/j.ejca.2006.01.003 PubMedCrossRef

30.

Mano Y, Aishima S, Fujita N, Tanaka Y, Kubo Y, Motomura T, Taketomi A, Shirabe K, Maehara Y, Oda Y (2013) Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma. Pathobiology 80(3):146–154. doi:10.1159/000346196 PubMedCrossRef

31.

Takaishi K, Komohara Y, Tashiro H, Ohtake H, Nakagawa T, Katabuchi H, Takeya M (2010) Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci 101(10):2128–2136. doi:10.1111/j.1349-7006.2010.01652.x PubMedCrossRef

32.

Chen JJ, Lin YC, Yao PL, Yuan A, Chen HY, Shun CT, Tsai MF, Chen CH, Yang PC (2005) Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol 23(5):953–964. doi:10.1200/JCO.2005.12.172 PubMedCrossRef

33.

Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66(2):605–612. doi:10.1158/0008-5472.CAN-05-4005 PubMedCrossRef

34.

Lewis JS, Landers RJ, Underwood JC, Harris AL, Lewis CE (2000) Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 192(2):150–158. doi:10.1002/1096-9896(2000)9999:9999<::AID-PATH687>3.0.CO;2-G PubMedCrossRef

35.

Valkovic T, Dobrila F, Melato M, Sasso F, Rizzardi C, Jonjic N (2002) Correlation between vascular endothelial growth factor, angiogenesis, and tumor-associated macrophages in invasive ductal breast carcinoma. Virchows Arch 440(6):583–588. doi:10.1007/s004280100458 PubMedCrossRef

36.

Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS, Bicknell R, Taylor M, Gatter KC, Harris AL (2002) Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in human breast cancer. Cancer Res 62(5):1326–1329PubMed

37.

Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104(8):2224–2234. doi:10.1182/blood-2004-03-1109 PubMedCrossRef

38.

Leek RD, Landers RJ, Harris AL, Lewis CE (1999) Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br J Cancer 79(5–6):991–995. doi:10.1038/sj.bjc.6690158 PubMedCentralPubMedCrossRef

39.

Aharinejad S, Abraham D, Paulus P, Abri H, Hofmann M, Grossschmidt K, Schafer R, Stanley ER, Hofbauer R (2002) Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice. Cancer Res 62(18):5317–5324PubMed

40.

De Palma M, Murdoch C, Venneri MA, Naldini L, Lewis CE (2007) Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. Trends Immunol 28(12):519–524. doi:10.1016/j.it.2007.09.004 PubMedCrossRef

41.

Huang H, Lai JY, Do J, Liu D, Li L, Del Rosario J, Doppalapudi VR, Pirie-Shepherd S, Levin N, Bradshaw C, Woodnutt G, Lappe R, Bhat A (2011) Specifically targeting angiopoietin-2 inhibits angiogenesis, Tie2-expressing monocyte infiltration, and tumor growth. Clin Cancer Res 17(5):1001–1011. doi:10.1158/1078-0432.CCR-10-2317 PubMedCrossRef

42.

Balkwill F, Mantovani A (2010) Cancer and inflammation: implications for pharmacology and therapeutics. Clin Pharmacol Ther 87(4):401–406. doi:10.1038/clpt.2009.312 PubMedCrossRef

Title: Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma
Authors: Carl Ludwig Behnes
Felix Bremmer
Bernhard Hemmerlein
Arne Strauss
Philipp Ströbel
Heinz-Joachim Radzun
Publication date: 01-02-2014
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 2/2014
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-013-1523-0

At a glance: The STEP trials

Springer Medicine

Tumor-associated macrophages are involved in tumor progression in papillary renal cell carcinoma

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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