CXCL10/CXCR3 overexpression as a biomarker of poor prognosis in patients with stage II colorectal cancer

Bai,Ming; Chen,Xia; Ba,Yi

doi:10.3892/mco.2015.665

CXCL10/CXCR3 overexpression as a biomarker of poor prognosis in patients with stage II colorectal cancer

Authors:
- Ming Bai
- Xia Chen
- Yi Ba
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Affiliations: Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China, Department of Pediatric Hematology Center, Institute of hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300041, P.R. China
Published online on: October 30, 2015 https://doi.org/10.3892/mco.2015.665
Pages: 23-30
Copyright: © Bai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The CXCL10/CXCR3 axis of inflammatory mediators is one of the most important groups of chemokine axes, which has been proven to be a lymphocyte‑associated metastasis mediator in several tumors. The term inflammatory adhesions refers to tumors found to be attached to the surrouding tissues during surgery, although no cancer cell infiltration is later identified on pathological examination. The aim of the present study was to investigate the clinical characteristics of stage II colorectal cancer (CRC) and determine the correlation between the CXCL10/CXCR3 axis, inflammatory adhesions and prognosis. Clinicohistopathological data were collected from 401 CRC patients who had undergone R0 resection. Statistical analysis was performed with SPSS 17.0 software. Immunohistochemistry (IHC) was applied to measure the expression of CXCL10 and CXCR3 in 71 recurrent CRC patients, 72 non‑recurrent CRC patients and 10 samples from normal peritumoral tissues, all retrieved from the Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. Inflammatory adhesions, tumor location and size and the number of high‑risk factors for reccurrence were more significantly associated with overall survival (OS) rather than disease-free survival in all the patients as determined by the log‑rank and Cox's regression hazard analysis. Further analysis demonstrated that only the presence of inflammatory adhesions (P=0.025) was associated with the OS of recurrent patients. Patients with recurrence exhibited higher CXCR3 (P<0.001) and CXCL10 (P<0.001) expression compared with non‑recurrent patients, as determined by IHC. The correlation between clinicopathological variables, CXCL10/CXCR3 expression and survival was also analyzed: Inflammatory adhesions and general tumor type (ulcerated vs. elevated) exhibited a significant correlation with CXCR3; however, the expression of CXCL10 was not significantly correlated with tumor location, histological type, size, gender, or preoperative carcinoembryonic antigen and hemoglobin levels. Furthermore, patients exhibiting a high expression of CXCR3 presented with a higher risk of relapse; among those, patients with inflammatory adhesions always exhibited worse survival. However, no such association was identified for CXCL10 expression. In conclusion, CXCR3 expression may be used as a prognostic marker and may contribute to the prediction of clinical outcome in stage II CRC patients.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Chambers AF, Groom AC and MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2:563–572. 2002. View Article : Google Scholar : PubMed/NCBI
3	Benson AB III, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, et al: American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 22:3408–3419. 2004. View Article : Google Scholar : PubMed/NCBI
4	Ribic CM, Sargent DJ, Moore MJ, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 349:247–257. 2003. View Article : Google Scholar : PubMed/NCBI
5	Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, et al: Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 28:3219–3226. 2010. View Article : Google Scholar : PubMed/NCBI
6	Zlotnik A: Chemokines in neoplastic progression. Semin Cancer Biol. 14:181–185. 2004. View Article : Google Scholar : PubMed/NCBI
7	Balkwill F: Cancer and the chemokine network. Nat Rev Cancer. 4:540–550. 2004. View Article : Google Scholar : PubMed/NCBI
8	Dwinell MB, Lügering N, Eckmann L and Kagnoff MF: Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology. 120:49–59. 2001. View Article : Google Scholar : PubMed/NCBI
9	Kawada K, Hosogi H, Sonoshita M, Sakashita H, Manabe T, Shimahara Y, Sakai Y, Takabayashi A, Oshima M and Taketo MM: Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene. 26:4679–4688. 2007. View Article : Google Scholar : PubMed/NCBI
10	Zhang R, Zhang H, Zhu W, Pardee AB, Coffey RJ Jr and Liang P: Mob-1, a Ras target gene, is overexpressed in colorectal cancer. Oncogene. 14:1607–1610. 1997. View Article : Google Scholar : PubMed/NCBI
11	Jiang Z, Xu Y and Cai S: CXCL10 expression and prognostic significance in stage II and III colorectal cancer. Mol Biol Rep. 37:3029–3036. 2010. View Article : Google Scholar : PubMed/NCBI
12	Li ZS and Li Q: The latest 2010 WHO classification of tumors of digestive system. Zhonghua Bing Li Xue Za Zhi. 40:351–354. 2011.(In Chinese). PubMed/NCBI
13	Matsuda T, Seki T, Ogawara M, Miura R, Yokouchi M and Murakami M: Levels of beta-thromboglobulin and platelet factor 4 in various diseases (author's transl). J Jpn Hematol Soc. 43:871–878. 1980.(In Japanese).
14	Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gönner U, Wilsberg V, Junginger T, Berger MR, Galle PR and Moehler M: Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res. 11:1743–1750. 2005. View Article : Google Scholar : PubMed/NCBI
15	Ottaiano A, Franco R, Aiello Talamanca A, Liguori G, Tatangelo F, Delrio P, Nasti G, Barletta E, Facchini G, Daniele B, et al: Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II–III colorectal cancer patients. Clin Cancer Res. 12:2795–2803. 2006. View Article : Google Scholar : PubMed/NCBI
16	Correale P, Rotundo MS, Botta C, Del Vecchio MT, Ginanneschi C, Licchetta A, Conca R, Apollinari S, De Luca F, Tassone P, et al: Tumor infiltration by T lymphocytes expressing chemokine receptor 7 (CCR7) is predictive of favorable outcome in patients with advanced colorectal carcinoma. Clin Cancer Res. 18:850–857. 2012. View Article : Google Scholar : PubMed/NCBI
17	Li J, Sun R, Tao K and Wang G: The CCL21/CCR7 pathway plays a key role in human colon cancer metastasis through regulation of matrix metalloproteinase-9. Dig Liver Dis. 43:40–47. 2011. View Article : Google Scholar : PubMed/NCBI
18	Cabioglu N, Yazici MS, Arun B, Broglio KR, Hortobagyi GN, Price JE and Sahin A: CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin Cancer Res. 11:5686–5693. 2005. View Article : Google Scholar : PubMed/NCBI
19	Nakata B, Fukunaga S, Noda E, Amano R, Yamada N and Hirakawa K: Chemokine receptor CCR7 expression correlates with lymph node metastasis in pancreatic cancer. Oncology. 74:69–75. 2008. View Article : Google Scholar : PubMed/NCBI
20	Sato E, Fujimoto J, Toyoki H, Sakaguchi H, Alam SM, Jahan I and Tamaya T: Expression of IP-10 related to angiogenesis in uterine cervical cancers. Br J Cancer. 96:1735–1739. 2007. View Article : Google Scholar : PubMed/NCBI
21	Antonicelli F, Lorin J, Kurdykowski S, et al: CXCL10 reduces melanoma proliferation and invasiveness in vitro and in vivo. Br J Dermatol. 164:720–728. 2011. View Article : Google Scholar : PubMed/NCBI
22	Robledo MM, Bartolome RA, Longo N, Rodríguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sánchez-Mateos P and Teixidó J: Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. J Biol Chem. 276:45098–45105. 2001. View Article : Google Scholar : PubMed/NCBI
23	Zipin-Roitman A, Meshel T, Sagi-Assif O, Shalmon B, Avivi C, Pfeffer RM, Witz IP and Ben-Baruch A: CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. Cancer Res. 67:3396–3405. 2007. View Article : Google Scholar : PubMed/NCBI
24	Kawada K, Hasegawa S, Murakami T, Itatani Y, Hosogi H, Sonoshita M, Kitamura T, Fujishita T, Iwamoto M, Matsumoto T, et al: Molecular mechanisms of liver metastasis. Int J Clin Oncol. 16:464–472. 2011. View Article : Google Scholar : PubMed/NCBI
25	Metzner B, Hofmann C, Heinemann C, Zimpfer U, Schraufstätter I, Schöpf E and Norgauer J: Overexpression of CXC-chemokines and CXC-chemokine receptor type II constitute an autocrine growth mechanism in the epidermoid carcinoma cells KB and A431. Oncol Rep. 6:1405–1410. 1999.PubMed/NCBI
26	Hu B, Elinav E, Huber S, Strowig T, Hao L, Hafemann A, Jin C, Wunderlich C, Wunderlich T, Eisenbarth SC, et al: Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc Natl Acad Sci USA. 110:9862–9867. 2013. View Article : Google Scholar : PubMed/NCBI
27	Guthrie GJ, Roxburgh CS, Richards CH, Horgan PG and McMillan DC: Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer. Br J Cancer. 109:131–137. 2013. View Article : Google Scholar : PubMed/NCBI
28	Vaiopoulos AG, Athanasoula KCH and Papavassiliou AG: NF-κB in colorectal cancer. J Mol Med (Berl). 1029–1037. 2013. View Article : Google Scholar : PubMed/NCBI
29	de Niet A, de Bruijne J, Plat-Sinnige MJ, Takkenberg RB, van Lier RA, Reesink HW and van Leeuwen EM: Upregulation of CXCR3 expression on CD8⁺ T cells due to the pervasive influence of chronic hepatitis B and C virus infection. Hum Immunol. 74:899–906. 2013. View Article : Google Scholar : PubMed/NCBI
30	Björkander S, Heidari-Hamedani G, Bremme K, Gunnarsson I and Holmlund U: Peripheral monocyte expression of the chemokine receptors CCR2, CCR5 and CXCR3 is altered at parturition in healthy women and in women with systemic lupus erythematosus. Scand J Immunol. 77:200–212. 2013. View Article : Google Scholar : PubMed/NCBI