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Serum Cytokine Profiling as a Diagnostic and Prognostic Tool in Ovarian Cancer: A Potential Role for Interleukin 7

Authors' Affiliations: Departments of ¹ Gynaecology, ² Medical Microbiology, Molecular Virology Section, and ³ Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; and ⁴ Department of Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California

Requests for reprints: Hans W. Nijman, Department of Gynaecologic Oncology, University Medical Center Groningen, P.O. 30.001, 9700 RB Groningen, the Netherlands. Phone: 31-503611649; Fax: 31-503611806; E-mail: h.w.nijman{at}og.umcg.nl.

	Abstract

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Purpose: To evaluate if serum cytokine levels could be used as diagnostic or prognostic markers in ovarian cancer.

Experimental Design: A cytokine bead array was done to simultaneously analyze 14 cytokines in the sera of 187 ovarian cancer patients with complete clinicopathologic data and follow-up, 45 patients with benign ovarian tumors, and 50 healthy controls. Serum levels of the well-known serum tumor marker CA-125 were routinely measured in all patients.

Results: Serum levels of CA-125, interleukin 6 (IL-6), IL-7, and IL-10 were elevated in ovarian cancer patients compared with patients with benign ovarian tumors. Analyzing the cytokines in combination with CA-125 showed that a combination of IL-7 and CA-125 serum levels could accurately predict 69% of the ovarian cancer patients, without falsely classifying patients with benign pelvic mass. The cytokines IL-6, IL-7, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), and IP-10 and CA-125 were associated with disease-free and overall survival in univariate analysis. In multivariate analysis, IL-7 and IP-10 were independent predictors of overall survival, although after inclusion of the clininopathologic parameters, only stage and residual disease remained as independent predictors of survival.

Conclusions: IL-7 levels were found to be strongly associated with ovarian cancer and could be used in combination with CA-125 to distinguish between malignant and benign ovarian tumors.

Ovarian cancer often only gives vague and nonspecific symptoms, as a result of which, most patients have advanced-stage disease at diagnosis. Hence, markers for screening and diagnosis are needed. However, reliable markers with high sensitivity and specificity have not yet been identified. An often-used marker is serum CA-125, which is elevated in more than 80% of the patients with advanced epithelial ovarian cancer. Elevated CA-125 levels are also found in 1% of healthy women and 6% of patients with benign ovarian disease; therefore, CA-125 alone is not sensitive and specific enough for screening or diagnosis of ovarian cancer (2, 3).

The majority of patients presenting with advanced-stage disease will have relapse of disease after initial treatment, which is mostly incurable. Classic predictors of survival in ovarian cancer are clinical parameters, such as tumor stage, age, residual tumor after surgery, histology, preoperative ascites, and CA-125 levels (4). To further individualize treatment, additional prognostic markers that predict the clinical course of the disease have to be found.

Serum cytokine levels have been investigated as diagnostic and prognostic markers in ovarian cancer. Cytokines are produced by a variety of hemopoietic and nonhemopoietic cell types and mediate and regulate immunity, inflammation, and hemopoiesis. Ovarian cancer cell lines and primary ovarian cancer cell cultures seem to produce tumor-promoting cytokines like interleukin 6 (IL-6) and IL-8 (5, 6). The interaction between tumor and immune system and the production of cytokines by the tumor itself can result in different local and systemic levels of cytokines in cancer patients (7). Previous studies showed that most cytokines are not independent prognostic markers, and individual cytokines are not specific enough for screening purposes (3, 8, 9).

Lately, a new technique, the cytokine bead array, has been developed for simultaneous analysis of multiple cytokines in serum samples. Serum levels of epidermal growth factor (EGF), monocyte chemotactic protein-1 (MCP-1), CA-125, vascular endothelial growth factor (VEGF), IL-6, and IL-8 showed significant differences between early-stage ovarian cancer and control groups based on this cytokine bead array. A panel of these cytokines resulted in a higher sensitivity and specificity than CA-125 alone in distinguishing early-stage ovarian cancer from control groups (10). However, in this study, serum cytokines were only investigated as a screening tool for early-stage ovarian cancer and not for use as diagnostic or prognostic tool.

In the present study, the cytokine bead array was used to analyze 14 cytokines in prospectively collected sera from ovarian cancer patients with complete clinicopathologic data and adequate follow-up. The aim of this study was to evaluate if levels of cytokines can distinguish patients with ovarian cancer from patients with benign ovarian tumors or healthy controls. The second aim was to determine whether cytokines can be used as prognostic markers in ovarian cancer.

	Materials and Methods

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Patients. Pretreatment and follow-up serum samples are routinely obtained of ovarian cancer patients treated at the Department of Gynecologic Oncology of the University Medical Center Groningen (Groningen, the Netherlands). After collection, serum is stored at –80°C in our serum bank until use. Serum markers like CA-125 are routinely determined in all patients suspected of ovarian cancer. In addition, extra serum is obtained after informed consent for future (research) use. The present study is part of an institutional review board–approved protocol (UMCG 2002/219). Patients who underwent surgery followed by chemotherapy at our department between January 1985 and July 2004 and of whom sufficient serum was still available were selected. Serum samples of 187 ovarian cancer patients before surgery and 3 to 6 months after chemotherapy were selected. Tumors are staged according to the International Federation of Gynecology and Obstetrics classification. All stages and histologic types are represented in this patient group and are a reflection of the regular population of ovarian cancer patients (Table 1 ). Data concerning age, tumor histology, tumor stage, differentiation grade, historical CA-125 values (all analyzed with the same assay), type of chemotherapy, response on chemotherapy, residual tumor, ascites, and clinical outcome were retrieved from our database (see next section). The mean observation period of ovarian cancer patients was 3.9 years (range 0-17.7 years). Preoperative sera of 45 patients with benign ovarian tumors and sera of 50 age-matched healthy females were analyzed as controls.

Selection of cytokines. For selection of cytokines to be measured, initially, preoperative serum of 26 ovarian cancer patients, postchemotherapy serum of 20 ovarian cancer patients, and serum of 12 patients with benign ovarian tumors and 8 healthy controls were analyzed for 21 cytokines [IL-1, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL12p70, IL-13, IL-15, IL-17, IFN-, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor- (TNF-), eotaxin, MCP-1, macrophage inflammatory protein-1 (MIP-1), and IP-10] by cytokine bead array. Cytokines with very low or undetectable concentrations in all patients in this group were excluded from further analyses. Serum samples of our entire patient population were subsequently analyzed for 14 cytokines with a customized LINCOplex kit.

Cytokine bead array. For the simultaneous measurement of multiple cytokines in a small volume of serum, a LINCOplex kit was used according to manufacturer's protocol (Linco research, St. Charles, MO). The serum samples were randomly assigned to the plates to avoid assay bias. Two serum samples were analyzed on every plate to determine interassay differences. A filter-bottom, 96-well microplate was blocked for 10 min with provided assay buffer. A standard curve (ranging from 3.2 to 10,000 pg/mL) was made by 5-fold dilutions of the human cytokine standard cocktail in the provided buffer. Standards, controls, and patient sera were pipetted at 25 µL per well in duplicate. About 25 µL of serum diluent was added to the standards and controls, and 25 µL of provided assay buffer was added to the serum samples. After adding 25 µL of the bead mixture, the microplate was incubated for 1 h on a microtiter shaker in the dark at room temperature. Wells were washed twice using a vacuum manifold. A cocktail of biotinylated secondary antibodies was added, and the microplate was incubated for 30 min in the dark on a microtiter shaker. After 30 min of incubation with streptavidin-phytoerythrin, the microplate was washed twice. Sheath fluid was added to each well, and samples were analyzed using the Bioplex system (Bio-Rad Laboratories, Hercules, CA). Data were analyzed using a five-parametric-curve fitting. As a control for freeze-thaw effects, serum was frozen and thawed up to seven times before analysis. No changes in cytokine concentrations were detected after these multiple freeze-thaw cycles.

Statistical analysis of data. Differences in cytokine levels between ovarian cancer patients, patients with benign ovarian tumors, and healthy controls were determined with a Mann-Whitney U test. To analyze differences in cytokine levels before operation compared with cytokine levels after primary treatment (surgery followed by chemotherapy), a Wilcoxon signed rank test was done. Tumor and clinical parameters were correlated with cytokine levels in ovarian cancer patients using a Mann-Whitney U test. Receiver-operator curves (ROC) were created to determine the predictive value of the cytokines to distinguish between ovarian cancer patients and control groups. Statistical differences in progression-free survival and overall survival for prognostic markers were determined by the log-rank test, and Kaplan-Meier survival curves were made. Overall survival was defined as the time since primary surgery until death due to ovarian cancer or the date of last follow-up. Progression-free survival was defined as the time from primary surgery until the date of progression or relapse of the disease. Multivariate analysis was done using the Cox's proportional hazard model. Statistical significance was defined as P < 0.05. SPSS (SPSS 1202 Inc., Chicago, IL) was used for all analyses.

	Results

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Selection of cytokines. Sera of a small group of ovarian cancer patients, patients with benign ovarian tumors, and healthy controls were analyzed for a panel of 21 cytokines by cytokine bead array. Serum concentrations of IL-1ß, IL-5, IL-12p70, IL-13, IL-17, TNF-, and IFN- were low or undetectable in all patients in this group and, therefore, not analyzed in the complete patient group. Subsequently, serum samples of all patients were analyzed for IL-1, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-15, G-CSF, GM-CSF, eotaxin, MCP-1, MIP-1, and IP-10.

Cytokine and CA-125 concentrations in pretreatment sera of ovarian cancer patients and control groups. Median serum levels of CA-125, IL-6, IL-7, IL-8, IL-10, and MCP-1 were higher in ovarian cancer patients compared with healthy controls (P < 0.001 to P < 0.03; Table 2 ). Sera of ovarian cancer patients had lower levels of G-CSF than healthy controls (P < 0.01). Serum levels of CA-125, IL-6, IL-7 and IL-10 were higher in ovarian cancer patients compared with patients with benign ovarian tumors (P < 0.001 to P < 0.02).

Pretreatment serum cytokine concentrations in relation to clinicopathologic parameters. Table 3 shows that serum levels of CA-125, IL-6, IL-7, IL-8, IL-10, eotaxin, MCP-1, and IP-10 were related with more advanced disease and presence of ascites (P < 0.001 to P < 0.04). CA-125, IL-6, IL-7, IL-8, IL-10, MCP-1, and IP-10 were related with residual tumor after surgery (P < 0.001 to P < 0.02). Serum CA-125, IL-8, IL-10, eotaxin, MCP-1, and IP-10 were higher in patients with serous tumors versus nonserous tumors (P <0.001 to P < 0.04). CA-125, IL-8, IL-10, eotaxin, and IP-10 were related with higher grade tumors (P < 0.001 to P < 0.03). IL-6, IL-8, IL-10, eotaxin, MCP-1, and IP-10 were related with increasing age (P < 0.001 to P < 0.02).

Predictive value of serum cytokines for ovarian cancer versus control groups. ROC were created to determine the predictive value of serum cytokines distinguishing ovarian cancer patients from control groups. Serum levels of cytokines (IL-6, IL-7, and IL-10) and CA-125 elevated in serum of ovarian cancer patients compared with patients with benign ovarian tumors were analyzed for their predictive value. Areas under the ROC for CA-125, IL-6, IL-7, and IL-10 were 0.881, 0.609, 0.721, and 0.695, respectively (P < 0.001 to P < 0.03, Fig. 1A and B ). CA-125 discriminated between benign ovarian tumors versus cancer with a sensitivity of 81.1% and a specificity of 80%. For IL-6, IL-7, and IL-10, the area under the curve was low, resulting in sensitivities and specificities between 60% and 70%. Serum levels of CA-125, IL-6, IL-7, IL-8, IL-10, and MCP-1 were significantly higher in ovarian cancer patients versus healthy controls and were analyzed for their diagnostic value. For ovarian cancer versus healthy controls, the areas under the curve for CA-125, IL-6, IL-7, IL-8, IL-10, and MCP-1 were 0.952, 0.602, 0.660, 0.618, 0.681, and 0.615, respectively (P < 0.03 to P < 0.001). CA-125 had a sensitivity of 90.9% and a specificity of 85.3% for distinguishing between cancer and healthy controls. CA-125 levels above the upper limit of normal (35,000 units/L) accurately classified 82% of the ovarian cancer patients, but also wrongly classified 27% of the patients with benign tumors as malignant. For the other cytokines, sensitivities and specificities between 55% and 70% were reached.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Serum cytokines for distinguishing between patients with malignant and benign ovarian tumors. A, ROC for CA-125. B, ROC for IL-6 (- - -), IL-7 (—), and IL-10 (—) for ovarian cancer versus benign ovarian tumors. C, combination of serum levels of IL-7 and CA-125 that can discriminate between patients with malignant or benign ovarian tumors. The markers with cutoff (picograms per milliliter for IL-7 and thousand units per liter for CA-125) are depicted, together with the percentage of the patients with malignant or benign tumors that were predicted by the combination of markers.

For stage I/II patients versus healthy controls, the areas under the curve for CA-125 and IP-10 were 0.875 and 0.352 (P < 0.001 and P < 0.06, respectively). For stage I/II ovarian cancer patients versus patients with benign ovarian tumors, the areas under the curve for CA-125, IL-7, eotaxin, and IP-10 were 0.716, 0.615, 0.364, and 0.362, respectively (P < 0.001 to P < 0.04; data not shown).

Serum cytokine levels as prognostic marker in ovarian cancer. Univariate analysis of the clinicopathologic parameters showed that age, histology, stage, grade, response to chemotherapy, residual tumor, and ascites were associated with progression-free and overall survival in ovarian cancer patients (Table 4 ). The type of chemotherapy that patients received (non-taxol–containing chemotherapy versus taxol/platinum-based chemotherapy) did not influence the overall or progression-free survival as determined by univariate analysis (P = 0.33 and P = 0.89, respectively). Serum levels of CA-125, IL-6, IL-7, IL-8, IL-10, MCP-1, and IP-10 above the median were associated with a shorter progression-free and overall survival in the univariate analysis (Table 4). Kaplan-Meier curves of IL-7 and IP-10 are shown in Fig. 2 , the other above-mentioned cytokines gave similar results.

View larger version (10K): [in this window] [in a new window]   Fig. 2. Kaplan-Meier curves of serum IL-7 levels (A) and serum IP-10 levels (B). The median IL-7 levels (5.3 pg/mL) and IP-10 level (110.5 pg/mL) were taken as cutoff points. Kaplan-Meier curves of serum CA-125, IL-6, IL-8, IL-10, and MCP-1 showed similar results.

In multivariate analysis of the clinicopathologic parameters, stage and tumor grade remained as independent predictors of progression-free survival in ovarian cancer patients. Stage and residual tumor were independent predictors of overall survival. Response on chemotherapy was evaluable in only 42% of the patients and, therefore, not included in the multivariate analysis. Multivariate analysis of the cytokines that were associated with survival in the univariate analysis revealed that IL-7 and IP-10 were independent predictors of overall survival. CA-125 and IP-10 were independent predictors of progression-free survival. However, when these cytokines were analyzed together with the clinicopathologic parameters, only stage and residual tumor remained independent predictors of progression-free and overall survival.

Furthermore, different combinations of cytokines, which showed correlation with survival in the univariate analysis, were analyzed. In the univariate analyses, a combination of CA-125, IL-7, and IP-10 with serum levels higher than the median gave the best association with overall survival, with a hazard ratio of 5.77 [95% confidence interval (95% CI), 2.88-11.53]. Although the hazard ratio of this panel of cytokines is higher than for the individual cytokines, the panel of CA-125, IL-7, and IP-10 was not an independent prognostic marker in the multivariate analysis.

	Discussion

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In our study, serum levels of CA-125, IL-6, IL-7, and IL-10 were found to be elevated in ovarian cancer compared with patients with benign ovarian tumors. Moreover, determination of both IL-7 levels and CA-125 could classify 69% of the ovarian cancer patients accurately, without falsely classifying patients with benign ovarian tumors. We and others found that the commonly used tumor marker CA-125 was elevated (>35,000 units/L) in 82% of the ovarian cancer patients (2). However, as has been shown by many previously, CA-125 was also elevated in part of the patients with benign tumors and, therefore, lacks sufficient sensitivity and specificity to be used solitarily for distinguishing between malignant and benign pelvic mass (11). To our knowledge, IL-7 has never been investigated for use as a diagnostic tool in ovarian cancer. Xie et al. reported that IL-7 was found to be expressed in only 3% of the ovarian carcinoma tissues (12), indicating that the increased serum levels of IL-7 probably are produced by host immune cells in response to tumor growth. In cervical and endometrial cancer, serum IL-7 was also elevated compared with healthy controls, but was not further investigated for diagnostic or prognostic purposes (13, 14). Our data suggest that IL-7 might be a good addition to CA-125 for diagnosis of malignant versus benign ovarian tumors. A prospective, larger study should be done to evaluate the additional value of determining IL-7 in combination with CA-125 for discriminating between benign and malignant pelvic masses. Naturally, in such a study, commonly used tools such as ultrasound should also be included.

In a variety of studies, IL-6 and IL-10 have also been reported to be elevated in serum or peritoneal fluids of ovarian cancer patients compared with patients with benign ovarian tumors (10, 12, 15, 16). IL-10 levels were measured to distinguish ovarian cancer from benign ovarian tumors, but a low sensitivity and specificity were reported (15), comparable to the data in the present study.

The second goal of the study was to determine if a single cytokine, or a combination of cytokines, could be used as a prognostic marker for ovarian cancer. In multivariate analysis, IL-7 and IP-10 were shown to be significant predictors of overall survival. However, after inclusion of the clinicopathologic parameters in the multivariate analysis, only stage and residual tumor remained independently related to overall survival, which is probably due to the relation between serum IL-7 and IP-10 levels and stage and residual disease. Thus, IL-7 and IP-10 are correlated with the course of the disease, but the relation is not strong enough to use these cytokines as independent prognostic markers in ovarian cancer.

IL-7 seemed to be one of the strongest prognostic markers of all cytokines tested in our study. In breast cancer patients, aberrant expression of IL-7 and its signaling intermediates have also been related to a poor prognosis (17). It was suggested that IL-7 affects breast tumors by acting as a growth factor for both endothelial and breast cancer cells and by promoting lymphangiogenesis and metastasis (17, 18). In contrast, transfection of IL-7 in an ovarian cancer cell line reduced tumorgenicity probably by activation of lymphokine-activated killer cells (12). In colorectal cancer tissue and cell lines, IL-7 was found to be produced by tumor cells and was able to expand tumor-infiltrating lymphocytes, thereby enhancing antitumor immunity (19). In ovarian cancer, further studies are required to address whether ovarian cancer cells are able to produce IL-7 and if IL-7 acts as a growth factor on ovarian cancer cells.

The cytokine bead array has been used in one study before for the early detection of ovarian cancer. The levels of the cytokines measured were similar to the levels measured by ELISA or RIA (10). In their study, the levels of CA-125, IL-6, IL-8, G-CSF, and MCP-1 were reported to be significantly different in early-stage ovarian cancer patients compared with control groups. We also found serum levels of CA-125, IL-6, IL-7, IL-8, IL-10, G-CSF, and MCP-1 to be elevated in ovarian cancer patients of all stages compared with healthy controls. Except for MCP-1, the concentration of these cytokines in healthy controls and patients with benign tumors were comparable to the concentrations as found by Gorelik et al., indicating that the cytokine bead array is reproducible.

In conclusion, IL-7 was found to be strongly related to ovarian cancer and may be used in combination with CA-125 for diagnosis of ovarian cancer. Its role in the course of ovarian cancer needs to be further explored.

	Footnotes

 
Grant support: Dutch Cancer Society grant 2002-2768 (H.W. Nijman), National Cancer Institute grant P30 CA14089 and the Beckman Center for Immune Monitoring at the University of Southern California (W.M. Kast). W.M. Kast holds the Walter A. Richter Cancer Research Chair.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: H.W. Nijman and W.M. Kast contributed equally as senior authors.

Received 7/25/06; revised 12/21/06; accepted 1/24/07.

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