Abstract
Purpose
The role of interleukin-17 (IL-17) in the tumor microenvironment is controversial. We analyzed the in situ tumor expression of IL-17 in colorectal cancer (CRC), adenoma and non-tumor tissue to explore the possible correlation of IL-17 expression to clinicopathological characteristics, tumor-infiltrating neutrophils (TINs) and survival in CRC.
Methods
We reviewed the records of 78 consecutive patients diagnosed with CRC. Archival tissues were used. Thirty-six patients with colorectal adenoma were also included. From the 78 CRC patients, we randomly chose 40 cases and collected non-tumor tissue at 10 cm from the edge of the resected tumor. Immunohistochemistry was performed using anti-IL-17 and anti-CD15 (targeting neutrophils) antibody, respectively. Real-time PCR was used to detect IL-17 mRNA in different tissues. Associations between IL-17 expression, clinicopathological parameters and prognosis were evaluated.
Results
The level of IL-17 mRNA was higher in CRC than in adenoma and non-tumor tissue (P < 0.05). Positive IL-17 protein expression was observed more frequently in CRC as compared to colorectal adenoma and non-tumor tissue, respectively (P < 0.01). IL-17 expression correlated to well differentiation and early stage CRC. The number of CD15+ neutrophils significantly increased in CRC and positively correlated to the expression of IL-17 (P < 0.05). Both Kaplan–Meier analysis and multivariate Cox regression analysis indicated that patients with positive IL-17 expression showed better overall survival.
Conclusions
The association between IL-17 expression and the clinicopathological parameters, as well as the clinical outcome suggests a significant role of IL-17 in CRC. IL-17 is a marker of favorable prognosis.
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References
Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–6.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.
Cui G, Yuan A, Goll R, Florholmen J. IL-17A in the tumor microenvironment of the human colorectal adenoma–carcinoma sequence. Scand J Gastroenterol. 2012;47:1304–12.
Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette MT, Berrehar F, et al. High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut. 2008;57:772–9.
Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol. 2009;50:980–9.
Olsen T, Rismo R, Cui G, Goll R, Christiansen I, Florholmen J. TH1 and TH17 interactions in untreated inflamed mucosa of inflammatory bowel disease, and their potential to mediate the inflammation. Cytokine. 2011;56:633–40.
Petanidis S, Anestakis D, Argyraki M, Hadzopoulou-Cladaras M, Salifoglou A. Differential expression of il-17, 22 and 23 in the progression of colorectal cancer in patients with k-ras mutation: ras signal inhibition and crosstalk with GM-CSF and IFN-gamma. PLoS One. 2013;8:e73616.
Kryczek I, Wei S, Szeliga W, Vatan L, Zou W. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood. 2009;114:357–9.
Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009;31:787–98.
Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 2008;112:362–73.
He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol. 2010;184:2281–8.
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71:1263–71.
Wakita D, Sumida K, Iwakura Y, Nishikawa H, Ohkuri T, Chamoto K, et al. Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis. Eur J Immunol. 2010;40:1927–37.
Xu S, Cao X. Interleukin-17 and its expanding biological functions. Cell Mol Immunol. 2010;7:164–74.
Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54:948–55.
Zhao JJ, Pan K, Wang W, Chen JG, Wu YH, Lv L, et al. The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS One. 2012;7:e33655.
Lin Y, Buckhaults PJ, Lee JR, Xiong H, Farrell C, Podolsky RH, et al. Association of the actin-binding protein transgelin with lymph node metastasis in human colorectal cancer. Neoplasia. 2009;11:864–73.
Mazumdar M, Glassman JR. Categorizing a prognostic variable: review of methods, code for easy implementation and applications to decision-making about cancer treatments. Stat Med. 2000;19:113–32.
Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008;453:1051–7.
Nieminen U, Jussila A, Nordling S, Mustonen H, Farkkila MA. Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case–control observational study based on registry data. Int J Cancer. 2014;134(1):189–96.
Rubin DT, Huo D, Kinnucan JA, Sedrak MS, McCullom NE, Bunnag AP, et al. Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case–control study. Clin Gastroenterol Hepatol. 2013;11(12):1601–8.
Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, et al. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun. 2011;407:348–54.
Lan C, Huang X, Lin S, Huang H, Cai Q, Lu J, et al. High density of IL-17-producing cells is associated with improved prognosis for advanced epithelial ovarian cancer. Cell Tissue Res. 2013;352:351–9.
Clark RA, Klebanoff SJ. Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system. J Exp Med. 1975;141:1442–7.
Colombo MP, Ferrari G, Stoppacciaro A, Parenza M, Rodolfo M, Mavilio F, et al. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. J Exp Med. 1991;173:889–97.
Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell. 2011;20:300–14.
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. 2009;16:183–94.
Droeser RA, Hirt C, Eppenberger-Castori S, Zlobec I, Viehl CT, Frey DM, et al. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. PLoS One. 2013;8:e64814.
Ilie M, Hofman V, Ortholan C, Bonnetaud C, Coelle C, Mouroux J, et al. Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer. 2012;118:1726–37.
Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol. 2009;27:4709–17.
Li YW, Qiu SJ, Fan J, Zhou J, Gao Q, Xiao YS, et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol. 2011;54:497–505.
Rao HL, Chen JW, Li M, Xiao YB, Fu J, Zeng YX, et al. Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS One. 2012;7:e30806.
Acknowledgments
This work was supported by the Fundamental Research Funds for the Central Universities (No. 11ykpy32, YL) and the Yat-Sen Scholarship for Young Scientist (YL).
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The authors declare no conflict of interest.
Ethical standard
The study has been performed in accordance with the ethical standards of the Declaration of Helsinki and its later amendments. The study was approved by the ethics committee of Sun Yat-sen Memorial Hospital. Written informed consent was obtained from each patient.
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Lin, Y., Xu, J., Su, H. et al. Interleukin-17 is a favorable prognostic marker for colorectal cancer. Clin Transl Oncol 17, 50–56 (2015). https://doi.org/10.1007/s12094-014-1197-3
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DOI: https://doi.org/10.1007/s12094-014-1197-3