Abstract
Expression of monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) and its significance has been demonstrated in some cancer cells in recent clinical studies. However, the role of tumor MCP-1 and CCR2 expression in non-small cell lung cancer (NSCLC) remains unknown. The aim of the present study was to investigate the prognostic significance of MCP-1 and CCR2 expression in NSCLC cells. The relationship between MCP-1 and CCR2 expression in NSCLC cancer cells was examined by immunohistochemical staining of surgical specimens from 134 patients. Sixty-five of these patients had follow-up records. Kaplan–Meier analysis and Cox regression model were used to assess overall survival according to the presence or absence of MCP-1 and CCR2 expression in tumor cells. MCP-1 was detected in cancer cells of 107 NSCLC (79.9 %) and CCR2 was detected in cancer cells of 39 NSCLC (29.1 %). MCP-1 expression was correlated with sex, smoking habits, histology, and tumor size. Presence of MCP-1 in tumor cells was associated with better overall survival (P = 0.018). By multivariate analysis, MCP-1 expression in cancer cells showed an independent prognostic factor for overall survival (P = 0.002, hazard ratio [HR] = 0.256, 95 % confidence interval [CI] = 0.106–0.616). There was no significant relationship between CCR2 expression in tumor cells and clinical and pathological characteristics. Also, no significant positive correlation between MCP-1 and CCR2 expression was revealed by Spearman correlation analysis. Our data indicate that MCP-1 is overexpressed in NSCLC cells. Its expression in cancer cells is associated with better survival in NSCLC patients.
Similar content being viewed by others
Abbreviations
- NSCLC:
-
Non-small cell lung cancer
- SCLC:
-
Small cell lung cancer
- MCP-1:
-
Monocyte chemoattractant protein-1
- CCR2:
-
CC chemokine receptor 2
- TAM:
-
Tumor-associated macrophages
- UICC:
-
International Union Against Cancer
- AJCC:
-
American Joint Committee on Cancer
- CCL2:
-
CC ligand 2
- MMP-9:
-
Matrix metalloprotease-9
- CTL:
-
Cytotoxic T cells
- IFN:
-
Interferon
- TNF:
-
Tumor necrosis factor
- IL-1:
-
Interleukin 1
- IL-2:
-
Interleukin 2
- SNP:
-
Single-nucleotide polymorphism
References
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2008. CA Cancer J Clin 59:225–249
Yang L, Parkin DM, Li LD, Chen YD, Bray F (2004) Estimation and projection of the national profile of cancer mortality in China: 1991–2005. Br J Cancer 90:2157–2166
Mulshine JL (2005) Clinical practice. Lung cancer screening. N Engl J Med 352:2714–2720
Visbal AL, Williams BA, Nichols FC 3rd (2004) Marks RS, Jett JR, Aubry MC, Edell ES, Wampfler JA, Molina JR, Yang P (2004) Gender differences in non-small-cell lung cancer survival: an analysis of 4618 patients diagnosed between 1997 and 2002. Ann Thorac Surg 78:209–215
Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949
Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ (1989) Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med 169:1485–1490
Nakashima E, Mukaida N, Kubota Y, Kuno K, Yasumoto K, Ichimura F, Nakanishi I, Miyasaka M, Matsushima K (1995) Human MCAF gene transfer enhances the metastatic capacity of a mouse cachectic adenocarcinoma cell line in vivo. Pharm Res 12:1598–1604
Zachariae CO, Anderson AO, Thompson HL, Appella E, Mantovani A, Oppenheim JJ, Matsushima K (1990) Properties of monocyte chemotactic and activating factor (MCAF) purified from a human fibrosarcoma cell line. J Exp Med 171:2177–2182
Lu Y, Cai Z, Galson DL, Xiao G, Liu Y, George DE, Melhem MF, Yao Z, Zhang J (2006) Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. Prostate 66:1311–1318
Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O’Brien T, Kerin MJ (200)7 Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 13: 5020–5027
Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S (2004) Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastrogenterol 99:1667–1674
Watanabe H, Miki C, Okugawa Y, Toiyama Y, Inoue Y, Kusunoki M (2008) Decreased expression of monocyte chemoattractant protein-1 predicts poor prognosis following curative resection of colorectal cancer. Dis Colon Rectum 51:1800–1805
Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, Pasquali C, Calori G, Pessi F, Sperti C, Di Carlo V, Allavena P et al (2003) The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 63:7451–7461
Lebrecht A, Hefler L, Tempfer C, Koelbl H (2001) Serum cytokine concentrations in patients with cervical cancer: interleukin-4, interferon-gamma, and monocyte chemoattractant protein-1. Gynecol Oncol 83:170–171
Hefler L, Tempfer C, Heinze G, Mayerhofer K, Breitenecker G, Leodolter S, Reinthaller A, Kainz C (1999) Monocyte chemoattractant protein-1 serum levels in ovarian cancer patients. Br J Cancer 81:855–859
Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ (2000) Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96:34–40
Robinson SC, Scott KA, Balkwill FR (2002) Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha. Eur J Immunol 32:404–412
Cai Z, Chen Q, Chen J, Lu Y, Xiao G, Wu Z, Zhou Q, Zhang J (2009) Monocyte chemotactic protein 1 promotes lung cancer-induced bone resorptive lesions in vivo. Neoplasia 11:228–236
Arenberg DA, Keane MP, DiGiovine B, Kunkel SL, Strom SR, Burdick MD, Iannettoni MD, Strieter RM (2000) Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol Immunother 49:63–70
Nagai E, Ogawa T, Kielian T, Ikubo A, Suzuki T (1998) Irradiated tumor cells adenovirally engineered to secrete granulocyte/macrophage-colony-stimulating factor establish antitumor immunity and eliminate preexisting tumors in syngeneic mice. Cancer Immunol Immunother 47:72–80
Nokihara H, Yanagawa H, Nishioka Y, Yano S, Mukaida N, Matsushima K, Sone S (2000) Natural killer cell-dependent suppression of systemic spread of human lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection in severe combined immunodeficient mice. Cancer Res 60:7002–7007
Detterbeck FC, Boffa DJ, Tanoue LT (2009) The new lung cancer staging system. Chest 136:260–271
Pitkin L, Luangdilok S, Corbishley C, Wilson PO, Dalton P, Bray D, Mady S, Williamson P, Odutoye T, Rhys Evans P, Syrigos KN, Nutting CM et al (2007) Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival. Br J Cancer 97:670–677
Zlotnik A, Yoahie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12:121–127
Jiang Y, Beller DI, Frendl G, Graves DT (1992) Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol 148:2423–2428
Huang S, Singh RK, Xie K, Gutman M, Berry KK, Bucana CD, Fidler IJ, Bar-Eli M (1994) Expression of the JE/MCP-1 gene suppresses metastatic potential in murine colon carcinoma cells. Cancer Immunol Immunother 39:231–238
Berencsi K, Rani P, Zhang T, Gross L, Mastrangelo M, Meropol NJ, Herlyn D, Somasundaram R (2011) In vitro migration of cytotoxic T lymphocyte derived from a colon carcinoma patient is dependent on CCL2 and CCR2. J Transl Med 9:33
Charo IF, Myers SJ, Herman A, Franci C, Connolly AJ, Coughlin SR (1994) Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci USA 91:2752–2756
Bartoli C, Civatte M, Pellissier JF, Figarella-Branger D (2001) CCR2A and CCR2B, the two isoforms of the monocyte chemoattractant protein-1 receptor are up-regulated and expressed by different cell subsets in idiopathic inflammatory myopathies. Acta Neuropathol 102:385–392
Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313–326
Vande Broek I, Leleu X, Schots R, Facon T, Vanderkerken K, Van Camp B, Van Riet I (2006) Clinical significance of chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival. Haematological 2006(91):200–206
Lu Y, Cai Z, Xiao G, Liu Y, Keller ET, Yao Z, Zhang J (2007) CCR2 expression correlates with prostate cancer progression. J Cell Biochem 101:676–685
Miotto D, Boschetto P, Bononi I, Milani G, Legorini C, Cavallesco G, Lo Cascio N, Zeni E, Fabbri LM, Mapp CE (2007) CC ligand 2 levels are increased in LPS-stimulated peripheral monocytes of patients with non-small cell lung cancer. Respir Med 101:1738–1743
Yang L, Shi GL, Song CX, Xu SF (2010) Relationship between genetic polymorphism of MCP-1 and non-small-cell lung cancer in the Han nationality of North China. Genet Mol Res 27:765–771
Rovin BH, Lu L, Saxena R (1999) A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem Biophys Res Commun 259:344–348
Page SH, Wright EK Jr, Gama L, Clements JE (2011) Regulation of CCL2 expression by an upstream TALE homeodomain protein-binding site that synergizes with the site created by the A-2578G SNP. PLoS One 6:e22052
Ghilardi G, Biondi ML, La Torre A, Battaglioli L, Scorza R (2005) Breast cancer progression and host polymorphisms in the chemokine system: role of the macrophage chemoattractant protein-1 (MCP-1) -2518 G allele. Clin Chem 51:452–455
Tse KP, Tsang NM, Chen KD, Li HP, Liang Y, Hsueh C, Chang KP, Yu JS, Hao SP, Hsieh LL, Chang YS (2007) MCP-1 promoter polymorphism at 2518 is associated with metastasis of nasopharyngeal carcinoma after treatment. Clin Cancer Re 13:6320–6326
Nesbit M, Schaider H, Miller TH, Herlyn M (2001) Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells. J Immunol 166:6483–6490
Brigati C, Noonan DM, Albini A, Benelli R (2002) Tumors and inflammatory infiltrates: friends or foes? Clin Exp Metastasis 19:247–258
Tsung K, Dolan JP, Tsung YL, Norton JA (2002) Macrophages as effector cells in interleukin 12-induced T-cell-dependent tumor rejection. Cancer Res 62:5069–5075
Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956
Johnsen M, Lund LR, Rømer J, Almholt K, Danø K (1998) Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol 10:667–671
Conflict of interest
The authors made no disclosure.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, Xw., Qin, X., Qin, C.Y. et al. Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance. Cancer Immunol Immunother 62, 563–570 (2013). https://doi.org/10.1007/s00262-012-1361-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-012-1361-y