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PLOS ONE  2012 

Increased Intratumoral Neutrophil in Colorectal Carcinomas Correlates Closely with Malignant Phenotype and Predicts Patients' Adverse Prognosis

DOI: 10.1371/journal.pone.0030806

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Background Substantial evidence suggests that the presence of inflammatory cells plays a critical role in the development and/or progression of human tumors. Neutrophils are the common inflammatory cells in tumors; however, the infiltration of intratumoral neutrophils in colorectal carcinoma (CRC) and its effect on CRC patients' prognosis are poorly understood. Methodology/Principal Findings In this study, the methods of tissue microarray and immunohistochemistry (IHC) were used to investigate the prognostic significance of intratumoral CD66b+ neutrophil in CRC. According to receiver operating characteristic curve analysis, the cutoff score for high intratumoral CD66b+ neutrophil in CRC was defined when the mean counts were more than 60 per TMA spot. In our study, high intratumoral CD66b+ neutrophil was observed in 104/229 (45.4%) of CRCs and in 29/229 (12.7%) of adjacent mucosal tissues. Further correlation analysis showed that high intratumoral neutrophil was positively correlated with pT status, pM status and clinical stage (P<0.05). In univariate survival analysis, a significant association between high intratumoral neutrophil and shortened patients' survival was found (P<0.0001). In different subsets of CRC patients, intratumoral neutrophil was also a prognostic indicator in patients with stage II, stage III, grade 2, grade 3, pT1, pT2, pN0 and pN1 (P<0.05). Importantly, high intratumoral neutrophil was evaluated as an independent prognostic factor in multivariate analysis (P<0.05). Conclusions/Significance Our results provide evidence that increased intratumoral neutrophil in CRC may be important in the acquisition of a malignant phenotype, indicating that the presence of intratumoral neutrophil is an independent factor for poor prognosis of patients with CRC.


[1]  O'Connell JB, Maggard MA, Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96: 1420–1425.
[2]  You WC, Jin F, Devesa S, Gridley G, Schatzkin A, et al. (2002) Rapid increase in colorectal cancer rates in urban Shanghai, 1972–97, in relation to dietary changes. J Cancer Epidemiol Prev 7: 143–146.
[3]  Obrand DI, Gordon PH (1997) Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Dis Colon Rectum 40: 15–24.
[4]  Zafirellis K, Agrogiannis G, Zachaki A, Gravani K, Karameris A, et al. (2008) Prognostic significance of VEGF expression evaluated by quantitative immunohistochemical analysis in colorectal cancer. J Surg Res 147: 99–107.
[5]  Mantovani A (2009) Cancer: Inflaming metastasis. Nature 457: 36–37.
[6]  Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313: 1960–1964.
[7]  Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124: 263–266.
[8]  Nathan C (2006) Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6: 173–182.
[9]  Mookerjee RP, Stadlbauer V, Lidder S, Wright GA, Hodges SJ, et al. (2007) Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 46: 831–840.
[10]  Shojaei F, Singh M, Thompson JD, Ferrara N (2008) Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci U S A 105: 2640–2645.
[11]  Eck M, Schmausser B, Scheller K, Brandlein S, Muller-Hermelink HK (2003) Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma. Clin Exp Immunol 134: 508–515.
[12]  Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, et al. (2009) Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 27: 4709–4717.
[13]  Mantovani A (2009) The yin-yang of tumor-associated neutrophils. Cancer Cell 16: 173–174.
[14]  Chua W, Charles KA, Baracos VE, Clarke SJ (2011) Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer 104: 1288–1295.
[15]  Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, et al. (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16: 183–194.
[16]  Li YW, Qiu SJ, Fan J, Zhou J, Gao Q, et al. (2011) Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54: 497–505.
[17]  Ilie M, Hofman V, Ortholan C, Bonnetaud C, Coelle C, et al. (2011) Predictive clinical outcome of the intratumoral CD66b-positive neutrophil- to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer. In press.
[18]  Jensen TO, Schmidt H, Moller HJ, Donskov F, Hoyer M, et al. (2011) Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer. In press.
[19]  Zhu W, Cai MY, Tong ZT, Dong SS, Mai SJ, et al. (2011) Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial-mesenchymaltransition. Gut. In press.
[20]  Cai MY, Tong ZT, Zheng F, Liao YJ, Wang Y, et al. (2011) EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies. Gut 60: 967–976.
[21]  Cai MY, Zhang B, He WP, Yang GF, Rao HL, et al. (2010) Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma. Cancer Sci 101: 1543–1549.
[22]  Grisham MB, Ware K, Gilleland HE Jr, Gilleland LB, Abell CL, et al. (1992) Neutrophil-mediated nitrosamine formation: role of nitric oxide in rats. Gastroenterology 103: 1260–1266.
[23]  Vermeer IT, Henderson LY, Moonen EJ, Engels LG, Dallinga JW, et al. (2004) Neutrophil-mediated formation of carcinogenic N-nitroso compounds in an in vitro model for intestinal inflammation. Toxicol Lett 154: 175–182.
[24]  Campregher C, Luciani MG, Gasche C (2008) Activated neutrophils induce an hMSH2-dependent G2/M checkpoint arrest and replication errors at a (CA)13-repeat in colon epithelial cells. Gut 57: 780–787.
[25]  McLean MH, Murray GI, Stewart KN, Norrie G, Mayer C, et al. (2011) The inflammatory microenvironment in colorectal neoplasia. PLoS One 6: e15366.
[26]  Sun Y, Yokoi K, Li H, Gao J, Hu L, et al. (2011) NGAL expression is elevated in both colorectal adenoma-carcinoma sequence and cancer progression and enhances tumorigenesis in xenograft mouse models. Clin Cancer Res 17: 4331–4340.
[27]  Hu L, Hittelman W, Lu T, Ji P, Arlinghaus R, et al. (2009) NGAL decreases E-cadherin-mediated cell-cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells. Lab Invest 89: 531–548.
[28]  Sun Z, Yang P (2004) Role of imbalance between neutrophil elastase and alpha 1-antitrypsin in cancer development and progression. Lancet Oncol 5: 182–190.
[29]  Coussens LM, Tinkle CL, Hanahan D, Werb Z (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103: 481–490.
[30]  Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, et al. (2011) Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 54: 948–955.
[31]  Nielsen HJ, Hansen U, Christensen IJ, Reimert CM, Brunner N, et al. (1999) Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. J Pathol 189: 487–495.


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