Society of University Surgeons| Volume 154, ISSUE 3, P512-520, September 2013

Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma


      CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC.


      The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed.


      Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P < .001), lymph node metastasis (pN factor; P = .001), pathologic stage (P < .001), lymphatic invasion (P = .010), and venous invasion (P = .001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P = .046, .009, .029, .010, and <.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P < .001) and disease-specific survival (P = .008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P = .008) was independent predictive factor for RFS.


      Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Zhang J.X.
        • Tong Z.T.
        • Yang L.
        • et al.
        PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma.
        International Journal of Cancer. 2013; 132: 2567-2577
        • Enzinger P.C.
        • Mayer R.J.
        Esophageal cancer.
        N Engl J Med. 2003; 349: 2241-2252
        • Takeuchi H.
        • Ikeuchi S.
        • Kitagawa Y.
        • et al.
        Pretreatment plasma fibrinogen level correlates with tumor progression and metastasis in patients with squamous cell carcinoma of the esophagus.
        J Gastroenterol Hepatol. 2007; 22: 2222-2227
        • Shih C.H.
        • Ozawa S.
        • Ando N.
        • et al.
        Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus.
        Clin Cancer Res. 2000; 6: 1161-1168
        • Ando N.
        • Kato H.
        • Igaki H.
        • et al.
        A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907).
        Ann Surg Oncol. 2012; 19: 68-74
        • Brenner B.
        • Ilson D.H.
        • Minsky B.D.
        Treatment of localized esophageal cancer.
        Semin Oncol. 2004; 31: 554-565
        • Stahl M.
        • Stuschke M.
        • Lehmann N.
        • et al.
        Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus.
        J Clin Oncol. 2005; 23: 2310-2317
        • Tahara M.
        • Ohtsu A.
        • Hironaka S.
        • et al.
        Clinical impact of criteria for complete response (CR) of primary site to treatment of esophageal cancer.
        Japan J Clin Oncol. 2005; 35: 316-323
        • Bonnetain F.
        • Bouche O.
        • Michel P.
        • et al.
        A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer.
        Ann Oncol. 2006; 17: 827-834
        • Rohatgi P.R.
        • Swisher S.G.
        • Correa A.M.
        • et al.
        Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus.
        Cancer. 2005; 104: 1349-1355
        • Yuan A.
        • Chen J.J.
        • Yao P.L.
        • Yang P.C.
        The role of interleukin-8 in cancer cells and microenvironment interaction.
        Front Biosci. 2005; 10: 853-865
        • Waugh D.J.
        • Wilson C.
        The interleukin-8 pathway in cancer.
        Clin Cancer Res. 2008; 14: 6735-6741
        • Jenkins G.J.
        • Mikhail J.
        • Alhamdani A.
        • et al.
        Immunohistochemical study of nuclear factor-kappaB activity and interleukin-8 abundance in oesophageal adenocarcinoma; a useful strategy for monitoring these biomarkers.
        J Clin Pathol. 2007; 60: 1232-1237
        • Emadi S.
        • Clay D.
        • Desterke C.
        • et al.
        IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation, and ploidy in myeloid metaplasia with myelofibrosis.
        Blood. 2005; 105: 464-473
        • Jiang Y.P.
        • Wu X.H.
        • Shi B.
        • et al.
        Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression.
        Gynecol Oncol. 2006; 103: 226-233
        • Heidemann J.
        • Ogawa H.
        • Dwinell M.B.
        • et al.
        Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2.
        J Biol Chem. 2003; 278: 8508-8515
        • O'Riordan J.M.
        • Abdel-latif M.M.
        • Ravi N.
        • et al.
        Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.
        Am J Gastroenterol. 2005; 100: 1257-1264
        • Hannelien V.
        • Karel G.
        • Jo V.D.
        • Sofie S.
        The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer.
        Biochim Biophys Acta. 2012; 1825: 117-129
        • Nguyen G.H.
        • Schetter A.J.
        • Chou D.B.
        • et al.
        Inflammatory and microRNA gene expression as prognostic classifier of Barrett's-associated esophageal adenocarcinoma.
        Clin Cancer Res. 2010; 16: 5824-5834
        • Krzystek-Korpacka M.
        • Matusiewicz M.
        • Diakowska D.
        • et al.
        Elevation of circulating interleukin-8 is related to lymph node and distant metastases in esophageal squamous cell carcinomas–implication for clinical evaluation of cancer patient.
        Cytokine. 2008; 41: 232-239
        • Oh D.S.
        • DeMeester S.R.
        • Vallbohmer D.
        • et al.
        Reduction of interleukin 8 gene expression in reflux esophagitis and Barrett's esophagus with antireflux surgery.
        Arch Surg. 2007; 142: 554-559
        • Wang B.
        • Hendricks D.T.
        • Wamunyokoli F.
        • Parker M.I.
        A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer.
        Cancer Res. 2006; 66: 3071-3077
        • Kondo S.
        • Yoneta A.
        • Yazawa H.
        • et al.
        Downregulation of CXCR-2 but not CXCR-1 expression by human keratinocytes by UVB.
        J Cell Physiol. 2000; 182: 366-370
        • Eck M.
        • Schmausser B.
        • Scheller K.
        • et al.
        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. 2003; 134: 508-515
        • Johnson K.
        • Aarden L.
        • Choi Y.
        • et al.
        The proinflammatory cytokine response to coagulation and endotoxin in whole blood.
        Blood. 1996; 87: 5051-5060
        • Johnson K.
        • Choi Y.
        • DeGroot E.
        • et al.
        Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation.
        J Immunol. 1998; 160: 5130-5135
        • Fujishima S.
        • Sasaki J.
        • Shinozawa Y.
        • et al.
        Serum MIP-1 alpha and IL-8 in septic patients.
        Intensive Care Med. 1996; 22: 1169-1175
        • Tanaka N.
        • Kikuchi E.
        • Matsumoto K.
        • et al.
        Prognostic value of plasma fibrinogen levels in patients with localized upper tract urothelial carcinoma.
        BJU Int. 2013; : 857-864
        • Palumbo J.S.
        • Kombrinck K.W.
        • Drew A.F.
        • et al.
        Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.
        Blood. 2000; 96: 3302-3309
        • Wenger R.H.
        • Rolfs A.
        • Marti H.H.
        • et al.
        Hypoxia, a novel inducer of acute phase gene expression in a human hepatoma cell line.
        J Biol Chem. 1995; 270: 27865-27870
        • Lawrence S.O.
        • Simpson-Haidaris P.J.
        Regulated de novo biosynthesis of fibrinogen in extrahepatic epithelial cells in response to inflammation.
        Thrombos Haemostas. 2004; 92: 234-243
        • Palumbo J.S.
        • Talmage K.E.
        • Massari J.V.
        • et al.
        Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.
        Blood. 2005; 105: 178-185
        • Kitadai Y.
        • Takahashi Y.
        • Haruma K.
        • et al.
        Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cells in nude mice.
        Br J Cancer. 1999; 81: 647-653
        • Asfaha S.
        • Dubeykovskiy A.N.
        • Tomita H.
        • et al.
        Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates inflammation and accelerates colon carcinogenesis.
        Gastroenterology. 2013; 144: 155-166
        • Dutta S.
        • Al-Mrabt N.M.
        • Fullarton G.M.
        • et al.
        A comparison of POSSUM and GPS models in the prediction of post-operative outcome in patients undergoing oesophago-gastric cancer resection.
        Ann Surg Oncol. 2011; 18: 2808-2817
        • Spite M.
        • Norling L.V.
        • Summers L.
        • et al.
        Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.
        Nature. 2009; 461: 1287-1291
        • Shimada H.
        • Ochiai T.
        • Okazumi S.
        • et al.
        Clinical benefits of steroid therapy on surgical stress in patients with esophageal cancer.
        Surgery. 2000; 128: 791-798