Intratumoral interleukin-6 predicts ascites formation in patients with epithelial ovarian cancer: A potential tool for close monitoring

Journal of Ovarian Research

David L. Morris¹  Gregory Robertson²  Ai-Qun Wei³  Afshin Amini¹  Samar Masoumi-Moghaddam¹ 

[1]Department of Surgery, St George Hospital, The University of New South Wales, Gray Street, Kogarah, Sydney NSW 2217, Australia

[2]Department of Gynecology Oncology, St George Hospital, The University of New South Wales, Gray Street, Kogarah, Sydney NSW 2217, Australia

[3]Department of Orthopedic Surgery, St. George Hospital, The University of New South Wales, Gray Street, Kogarah, Sydney NSW 2217, Australia

关键词: Overall survival;    Interleukin-6;    Epithelial ovarian cancer;    Disease free survival;    Chemorefractoriness;    Ascites;   

Others  :  1224699
DOI  :  10.1186/s13048-015-0183-x

 received in 2015-06-02, accepted in 2015-07-29,  发布年份 2015

【 摘 要 】

Background

The implication of IL-6 in the pathogenesis of epithelial ovarian cancer (EOC) is well documented. Accordingly, the clinicopathological significance of this cytokine in patients’ ascites fluid or serum has largely been investigated. Since the main source of IL-6 secreted into the biological fluids is the tumor tissue, this study was designed to investigate the status and possible clinical relevance of the IL-6 expression in an array of EOC tissue specimens.

Methods

Tissue samples obtained from ninety-eight consecutive patients with EOC were studied using immunohistochemistry. Clinicopathological characteristics and treatment related factors were collected from patient files. The relationship between the expression of the protein of interest and the study endpoints of disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. For evaluating the predictive value of IL-6, logistic regression and cox proportional hazards models were employed.

Results

An upregulation of IL-6 expression was observed in EOC tissues as compared with the normal samples (p < 0.0001). As regards the clinical relevance, IL-6 failed to predict OS, DFS and response to the platinum-based chemotherapy in EOC patients. In multivariate analysis, however, IL-6 was identified as an independent predictive factor for the development of post-treatment ascites (p:0.033).

Conclusions

Having the capability to predict the ascites formation, IL-6 might serve as a biomarker and a useful tool in EOC for monitoring purposes. IL-6 targeting for the prevention of the ascites development is a potential avenue for further investigation.

【 授权许可】

   
2015 Masoumi-Moghaddam et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Kulbe H, Chakravarty P, Leinster DA, Charles KA, Kwong J, Thompson RG et al.. A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res. 2012; 72(1):66-75.
• [2]Longuespee R, Boyon C, Desmons A, Vinatier D, Leblanc E, Farre I et al.. Ovarian cancer molecular pathology. Cancer Metastasis Rev. 2012; 31(3–4):713-32.
• [3]Matte I, Lane D, Laplante C, Rancourt C, Piche A. Profiling of cytokines in human epithelial ovarian cancer ascites. Am J Cancer Res. 2012; 2(5):566-80.
• [4]Heikkila K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer. 2008; 44(7):937-45.
• [5]Nash MA, Ferrandina G, Gordinier M, Loercher A, Freedman RS. The role of cytokines in both the normal and malignant ovary. Endocrine-Related Cancer. 1999; 6(1):93-107.
• [6]Lidor YJ, Xu FJ, Martinez-Maza O, Olt GJ, Marks JR, Berchuck A et al.. Constitutive production of macrophage colony-stimulating factor and interleukin-6 by human ovarian surface epithelial cells. Exp Cell Res. 1993; 207(2):332-9.
• [7]Watson JM, Berek JS, Martinez-Maza O. Growth inhibition of ovarian cancer cells induced by antisense IL-6 oligonucleotides. Gynecol Oncol. 1993; 49(1):8-15.
• [8]Lo CW, Chen MW, Hsiao M, Wang S, Chen CA, Hsiao SM et al.. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 2011; 71(2):424-34.
• [9]Wang Y, Niu XL, Qu Y, Wu J, Zhu YQ, Sun WJ et al.. Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cancer Lett. 2010; 295(1):110-23.
• [10]Obata NH, Tamakoshi K, Shibata K, Kikkawa F, Tomoda Y. Effects of interleukin-6 on in vitro cell attachment, migration and invasion of human ovarian carcinoma. Anticancer Res. 1997; 17(1A):337-42.
• [11]Chen VW, Ruiz B, Killeen JL, Coté TR, Wu XC, Correa CN et al.. Pathology and classification of ovarian tumors. Cancer. 2003; 97(S10):2631-42.
• [12]Odicino F, Pecorelli S, Zigliani L, Creasman WT. History of the FIGO cancer staging system. Int J Gynaecology Obstetrics. 2008; 101(2):205-10.
• [13]Masoumi-Moghaddam S, Amini A, Wei AQ, Robertson G, Morris DL. Sprouty 2 protein, but not Sprouty 4, is an independent prognostic biomarker for human epithelial ovarian cancer. Int J Cancer. 2015; 137(3):560-70.
• [14]Mattern J, Koomagi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br J Cancer. 1996; 73(7):931-4.
• [15]Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P et al.. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology. 1998; 32(2):133-8.
• [16]Wang Y, Li L, Guo X, Jin X, Sun W, Zhang X et al.. Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells. Cytokine. 2012; 59(2):228-36.
• [17]Glezerman M, Mazot M, Maymon E, Piura B, Prinsloo I, Benharroch D et al.. Tumor necrosis factor-alpha and interleukin-6 are differently expressed by fresh human cancerous ovarian tissue and primary cell lines. Eur Cytokine Netw. 1998; 9(2):171-9.
• [18]Acien P, Ortola C, Barbal A, Quereda F, Dosda MD, Mauri M et al.. Comparative study of the diagnostic value of several tumor markers and hormonal determinations in ovarian neoplasms. Progresos en Obstetricia y Ginecologia. 1994; 37(3):163-70.
• [19]Gorelik E, Landsittel DP, Marrangoni AM, Modugno F, Velikokhatnaya L, Winans MT et al.. Multiplexed immunobead-based cytokine profiling for early detection of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2005; 14(4):981-7.
• [20]Plante M, Rubin SC, Wong GY, Federici MG, Finstad CL, Gastl GA. Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer. 1994; 73(7):1882-8.
• [21]Berek JS, Chung C, Kaldi K, Watson JM, Knox RM, Martinez-Maza O. Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. Am J Obstet Gynecol. 1991; 164(4):1038-42.
• [22]Dobrzycka B, Mackowiak-Matejczyk B, Terlikowska KM, Kulesza-Bronczyk B, Kinalski M, Terlikowski SJ. Serum levels of IL-6, IL-8 and CRP as prognostic factors in epithelial ovarian cancer. Eur Cytokine Netw. 2013; 24(3):106-13.
• [23]Kryczek I, Grybos M, Karabon L, Klimczak A, Lange A. IL-6 production in ovarian carcinoma is associated with histiotype and biological characteristics of the tumour and influences local immunity. Br J Cancer. 2000; 82(3):621-8.
• [24]Kutteh WH, Kutteh CC. Quantitation of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 in the effusions of ovarian epithelial neoplasms. Am J Obstet Gynecol. 1992; 167(6):1864-9.
• [25]Scambia G, Testa U, Benedetti Panici P, Foti E, Martucci R, Gadducci A et al.. Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer. 1995; 71(2):354-6.
• [26]Plewka D, Kowalczyk AE, Jakubiec-Bartnik B, Morek M, Bogunia E, Kmiec A et al.. Immunohistochemical visualization of pro-inflammatory cytokines and enzymes in ovarian tumors. Folia Histochem Cytobiol. 2014; 52(2):124-37.
• [27]Guo YQ, Lu P, Duan ZF, Zhang Z. Effects of siltuximab on the interleukin-6/Stat3 signaling pathway in ovarian cancer. Zhonghua Fu Chan Ke Za Zhi. 2010; 45(11):854-9.
• [28]Coward J, Kulbe H, Chakravarty P, Leader D, Vassileva V, Leinster DA et al.. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 2011; 17(18):6083-96.
• [29]Scambia G, Testa U, Panici PB, Martucci R, Foti E, Petrini M et al.. Interleukin-6 serum levels in patients with gynecological tumors. Int J Cancer. 1994; 57(3):318-23.
• [30]Cohen S, Bruchim I, Graiver D, Evron Z, Oron-Karni V, Pasmanik-Chor M et al.. Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2. J Molec Med (Berlin, Germany). 2013; 91(3):357-68.
• [31]Wang Y, Qu Y, Zhang XL, Xing J, Niu XL, Chen X et al.. Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1. Mol Cell Endocrinol. 2014; 382(2):791-803.
• [32]Puiffe ML, Le Page C, Filali-Mouhim A, Zietarska M, Ouellet V, Tonin PN et al.. Characterization of ovarian cancer ascites on cell invasion, proliferation, spheroid formation, and gene expression in an in vitro model of epithelial ovarian cancer. Neoplasia (New York, NY). 2007; 9(10):820-9.
• [33]Carmignani CP, Sugarbaker TA, Bromley CM, Sugarbaker PH. Intraperitoneal cancer dissemination: mechanisms of the patterns of spread. Cancer Metastasis Rev. 2003; 22(4):465-72.
• [34]Pourgholami MH, Ataie-Kachoie P, Badar S, Morris DL. Minocycline inhibits malignant ascites of ovarian cancer through targeting multiple signaling pathways. Gynecol Oncol. 2013; 129(1):113-9.