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Abstract

BACKGROUND:

Early detection and differentiation diagnosis of a pelvic mass (PM) is crucial in improving the prognosis of patients with epithelial ovarian cancer (EOC). C-C motif chemokine ligand 18 (CCL18) was reported as a chemokine-mediated tumor-related inflammation that can be detected in serum and may correlate with cancer patients’ prognosis.

OBJECTIVE:

We performed this study to investigate the relationship between CCL18 levels and clinical characteristics of EOC patients, and to explore their diagnostic and prognostic values.

METHODS:

CCL18 serum concentrations were detected by ELISA in 187 patients with EOC, 126 patients with benign PMs, and 118 healthy controls. CCL18 serum levels were analyzed in the context of patients’ clinicopathological information, and ROC analyses were performed to determine the effect of CCL18 on distinguishing benign and malignant PMs. The ability of CCL18 to serve as an EOC biomarker was compared with CA125. Further survival analyses were carried out to assess the prognostic value of CCL18 in EOC patients.

RESULTS:

Mean serum CCL18 levels were elevated in benign PM patients and were even higher in EOC patients than in healthy controls; furthermore, high CCL18 expression was associated with worse International Federation of Gynecology and Obstetrics (FIGO) staging and predicted a poorer survival of the patient. When compared with CA125, although the sensitivity and negative predictive values (NPV) of serum CCL18 were lower, its specificity and positive predictive values (PPV) were higher.

CONCLUSIONS:

Serum CCL18 was elevated in patients with EOC and could serve as a new tumor biomarker, which also predicted a poor survival of the patient.

Keywords

CCL18 ovarian cancer prognosis biomarker CA125

1. Introduction

Ovarian cancer (OC) is among the top ten malignancies in female, both internationally and in China [1, 2]. Although ovarian cancer is not the worst threatening gynecological cancer, the low early diagnostic rate and the obvious tumor heterogeneity still make the treatment one of the biggest challenges for gynecologic oncologists [3]. Ninety percent of ovarian cancer cases are epithelial ovarian cancer (EOC), who were often diagnosed in advanced-stage (FIGO III to IV); the screening and diagnosis of EOC at present mainly depend on imaging examination combined with serological examination [4, 5]. Because of the enormous difference between the survival rates of patients with early- (FIGO I to II) and advanced-stage (FIGO III to IV) EOC [6], early diagnosis is critical for patients with ovarian cancer.

The absence of typical clinical symptoms makes EOC difficult to detect and diagnose early, therefore serum tumor markers play important role in EOC diagnosis. The most widely used EOC serum tumor markers are CA125 and HE4 [7]. Although researchers have made every effort to improve the diagnosis efficiency, neither CA125 nor HE4 has ideal sensitivity or specificity in differentiating benign and malignant pelvic masses (PM) individually. Furthermore, although the risk of ovarian malignancy algorithm (ROMA), which is calculated using CA125 and HE4, provides a reliable diagnostic index, it shows neither prognostic nor therapeutic effect observation value for patients with EOC [8]. Searching for an effective serum tumor marker is still the main direction of pelvic-mass differential diagnosis [9, 10, 11].

C-C motif chemokine ligand 18 (CCL18) is a cytokine that can be detected easily in serum [12] and other body fluids by ELISA [13, 14]. Studies have shown elevated expression serum CCL18 in several cancers correlated with poor prognosis for patients, such as breast cancer [15], non-small-cell lung cancer [16], and pancreatic ductal adenocarcinoma (PDAC) [17]. Thus far, there have been few reports on the expression of CCL18 in ovarian cancer. Meng and colleagues demonstrated that CCL18 was significantly elevated in ascitic fluid collected from patients with ovarian cancer [18]. Two teams, Zohny’s and Wang’s, tried to clarify the utility of serum CCL18 combined with other serum markers, such as MMP-7, CCL11, CXCL1, and CA125, as biomarkers of EOC, but both were deficient in terms of the sample size studied [19, 20]. In our study, we detected serum CCL18 concentration in 126 benign PM specimens, 187 EOC specimens, and 118 healthy controls to investigate the capability of CCL18 as a biomarker to differential diagnose a PM and predict the prognosis of patients with EOC; such a marker could play an important role in improving EOC treatment.

2. Materials and methods

2.1 Subjects

The blood serum samples of 187 patients, aged 18 to 82 years (mean 50.6 $\pm$ 12.0 years) with a diagnosis of EOC; 126 patients with a benign PM, aged 19 to 66 years (mean 45.3 $\pm$ 14.2 years); and 118 healthy controls, aged 19 to 80 years (mean 47.5 $\pm$ 15.0 years) were investigated in this study. Patients with acute infection, liver dysfunction, renal insufficiency, chronic pulmonary disease, chronic cardiac insufficiency, autoimmune disease, post-organ transplantation, or previous malignancy were excluded. All EOC patients received standard treatment between September 2012 and April 2014 in the Department of Gynaecology at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. The histologic type and grade of all specimens were evaluated by pathological examination according to the World Health Organization (WHO) Classification of Tumours of Female Reproductive Organs, Fourth Edition. Patients’ clinical information was obtained from clinical charts, and the diagnosis were confirmed by at least two pathologists experienced in the specialty of gynecologic oncology. The disease of all the patients was staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging guideline 2014. Of the 187 cases of EOC with different kinds of pathological types, 78 cases of serous carcinoma, 41 cases of mucinous carcinoma, 40 cases of endometrioid carcinoma, 21 cases of clear cell carcinoma, and 7 cases of undifferentiated carcinoma were staged. There were 62 (33.1%) cases of stage I–II, and 125 (66.9%) cases of stage III–IV. Participants with a benign PMs were diagnosed with simple epithelial ovarian cysts ( $n=$ 36), endometriosis ( $n=$ 29), uterine leiomyoma ( $n=$ 40), and teratoma ( $n=$ 21). The healthy controls included 118 age-matched healthy participants who underwent a routine annual health checkup at the Physical Health Examination Center of the First Affiliated Hospital of Sun Yat-sen University. Other clinicopathological information is provided in Table 1. This study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University according to the guidelines of the Helsinki Convention. All the participants provided their informed consent.

Table 1
Clinicopathological variables of the normal controls, benign PMs, and ovarian cancer patients ( $n$ , %)

Variables	Normal controls	(%)	Benign PM	(%)	Ovarian cancer	(%)
	( $n=$ 118)		( $n=$ 126)		( $n=$ 187)
Age (years)	47.5 $\pm$ 15.0		45.3 $\pm$ 14.2		50.6 $\pm$ 12.0
Menopausal status
Premenopausal	69	58.5	76	60.3	107	57.2
Postmenopausal	49	41.5	50	39.7	80	42.8
FIGO stage
I $+$ II					62	33.1
III $+$ IV					125	66.9
Primary tumor type
Ovary					160	85.6
Fallopian tube					16	8.6
Peritoneum					11	5.8
Histological type
Serous					78	41.7
Mucinous					41	21.9
Endometrioid					40	21.4
Clear cell					21	11.2
Other					7	3.7
Grade
1					31	16.6
2					113	60.4
3					43	23.0
Lymph node metastases
Negative					91	48.7
Positive					96	51.3

2.2 Measurement of serum CCL18 and CA125 levels

All blood samples were collected prior to initial treatment. To avoid the effects of diet on the measurement of serum biomarkers, participants were told to fast overnight at least for 8 hours, and blood samples were obtained in the morning between 7 a.m. and 10 a.m. by venipuncture (BD Vacutainer Plus). Blood samples were allowed to clot at room temperature, centrifuged at 3000 rpm for 15 min immediately, and then tested in the clinical laboratory of the hospital within 2 hours. Samples with hemolysis were excluded from the study. Serum CCL18 was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) commercial kit (R&D Systems, MN, USA), according to the manufacturer’s instructions. Serum CA125 was measured by the ARCHITECT CA125 II assay (Abbott Diagnostics, Abbott Park, IL, USA) according to the manufacturer’s instructions. The cut-off value of CA125 was 35 U/mL, as recommended by the manufacturer.

2.3 Data collection and follow-up

All participants’ data were obtained from an combination of clinic, medical, and pathologic records, including age, menopausal status, FIGO stage, primary tumor type, histological type, grade, lymph node status, and survival data. All participants with EOC were followed up every 3 months for the first 2 years and every 6 months for the next 3 years until death or the cut-off date of May 31, 2016, and follow-up time ranged from 2 to 40 months.

2.4 Statistical analysis

The statistical analysis was performed using SPSS (version 13.0, SPSS Inc., Chicago, IL, USA). All variables with normal distributions were expressed as mean $\pm$ standard deviation (SD). The differences between groups were analyzed by the Mann-Whitney U test. The diagnostic performance of CCL18 was evaluated by nonparametric receiver operating characteristic (ROC) curves, sensitivity, specificity, area under the ROC curve (AUC), and with 95% confidence intervals (CI). The cut-off value of CCL18 was calculated by Youden’s index, the peak point of sensitivity $+$ specificity-1, according to all points of an ROC curve, and served as a standard for choosing the most suitable cut-off value. Patient outcome in overall survival (OS) was calculated by the Kaplan-Meier curve, and significant differences in the survival rate were calculated using the log-rank test. Time to death was evaluated by the Cox proportional hazards regression model for univariate and multivariate analyses. In all cases, $P<$ 0.05 was considered statistically significant, and all tests were performed two-tailed tests.

3. Results

3.1 Serum CCL18 levels in patients with EOC, benign PM, and healthy controls

Serum from 187 patients with EOC, 126 patients with benign PM, and 118 healthy controls was analyzed for CCL18 concentrations. The distributions of CCL18 concentrations in the three cohorts studied are shown in Fig. 1; the mean level of serum CCL18 was significantly elevated in patients with EOC compared to that in patients with benign PM and healthy controls (all $P<$ 0.0001). The mean serum CCL18 levels were 144.8 $\pm$ 104.2 ng/mL in patients with EOC, 49.3 $\pm$ 39.3 ng/mL in patients with benign PM, and 32.9 $\pm$ 11.9 ng/mL in healthy controls. Table 2 shows the correlations between CCL18 serum levels and clinicopathologic variables in EOC patients. Serum levels of CCL18 were associated with FIGO stage; patients with advanced stages had higher levels of serum CCL18 than those with early stages (156.5 $\pm$ 107.7 ng/mL in stage III $+$ IV, 120.1 $\pm$ 89.5 ng/mL in stage I $+$ II, $P=$ 0.01). In addition, there were no associations between serum CCL18 levels and other clinicopathologic variables (Table 2).

Table 2
The relationship between serum CCL18 levels and clinicopathological variables of the ovarian cancer patients group

Variables	Number	CCL18		$P$
		(mean $\pm$ SD, ng/mL)
Normal control	118	32.9	$\pm$ 11.9
Benign PM	126	49.3	$\pm$ 39.3	$<$ 0.	0001
Ovarian cancer	187	144.8	$\pm$ 104.2
Menopausal status
Premenopausal	107	150.4	$\pm$ 106.6	0.	5340
Postmenopausal	80	137.5	$\pm$ 101.1
FIGO stage
I $+$ II	62	120.1	$\pm$ 89.5	0.	01
III $+$ IV	125	156.5	$\pm$ 107.7
Primary tumor type
Ovary	160	143.8	$\pm$ 104.3	0.	7391
Other	27	150.9	$\pm$ 105.2
Histological type
Serous	78	146.5	$\pm$ 104.1	0.	7751
Other	109	141.7	$\pm$ 105.0
Grade
1	31	133.5	$\pm$ 103.9	0.	2981
2	113	154.3	$\pm$ 106.2
3	43	128.0	$\pm$ 97.9
Lymph node metastases
Negative	91	130.5	$\pm$ 96.3	0.	0507
Positive	96	160.1	$\pm$ 110.4

Figure 1.

Serum CCL18 levels in healthy controls, patients with benign PM, and patients with EOC. All data are presented as mean $\pm$ SD. ${}^{*}$ $P<$ 0.0001.

3.2 Performance of serum CCL18 in diagnosis of EOC patients

To evaluate the performance of serum CCL18 in PM differential diagnosis, receiver operating characteristic (ROC) curve analysis was performed among EOC patients, benign PM participants, and healthy controls. When we assessed the possibility of distinguishing EOC patients from healthy controls, the ROC area under the curve (AUC) was 0.876 (specificity: 0.983, sensitivity: 0.826, cut-off value: 55.38 ng/mL, Fig. 2A). When we calculated the power of differentiating benign PM from healthy controls, the AUC was 0.639 (specificity: 0.958, sensitivity: 0.286, cut-off value: 51.37 ng/mL, Fig. 2B). When we further evaluated the diagnostic value for EOC from benign PM, the AUC was 0.802 (specificity: 0.889, sensitivity: 0.679, cut-off value: 68.29 ng/mL, Fig. 2C). Next, the cut-off value of 55.38 ng/mL of serum CCL18 (EOC patients vs. healthy controls) was applied for further study. We compared the diagnostic performance of serum CCL18 with CA125 in EOC patients. As shown in Table 3, CCL18 had a lower sensitivity and negative predictive values (NPV) than CA125. While the specificity and positive predictive values (PPV) of CCL18 were higher than those of CA125 for the EOC group than for the controls (Table 3), CCL18 $+$ CA125 display more higher sensitivity and NPV than single biomarker, which suggested CCL18 could complement CA125 for diagnosis EOC. We then correlated CCL18 with CA125 serum levels in the same EOC patients. As displayed in Fig. 3, a significant inverse correlation was founded when CCL18 were plotted against CA125 (2-tailed Spearman’s correlation, $r=-$ 0.3520, $P<$ 0.0001).

Table 3
Diagnosis values of different biomarkers for women with ovarian cancer, benign PMs or normal healthy controls. Positive and negative predictive values (PPV and NPV). CCL18, cutoff value 55.4 ng/mL, CA125, cut off value 35 U/mL

Marker	Groups	Samples	Samples	Total number	Sens (%)	Spec (%)	PPV (%)	NPV (%)
		below cut-off	above cut-off	of samples
		(low risk)	(high risk)
CCL18	Controls	115	3	118		97.5	97.8	69.2
	Benign PM	96	30	126		76.2	81.9	65.3
	EOC	51	136	187	72.7
CA125	Controls	99	19	118		83.9	89.7	82.5
	Benign PM	97	29	126		77.0	85.1	82.2
	EOC	21	166	187	88.8
CCL18 $+$	Controls	97	21	118		82.2	89.2	87.4
CA125	Benign PM	74	52	126		58.7	76.9	84.1
	EOC	14	173	187	92.5

Figure 2.

ROC analysis showing the area under curve of serum CCL18 to distinguish (A) EOC patients from healthy controls, (B) patients with PM from healthy controls, and (C) patients with EOC from patients with PM. NC: normal healthy controls; PM: PM.

Figure 3.

Correlation between serum CCL18 and CA125 in patients with EOC.

3.3 High serum CCL18 levels predict poor prognosis for patients with EOC

To visualize the prognostic relevance of serum CCL18, we applied the mean serum CCL18 levels of EOC patients, 144.8 ng/mL, as a set point to divide 187 cases of patients with EOC into a high serum CCL18 level group ( $\geqslant$ 144.8 ng/mL) and a low serum CCL18 level group ( $<$ 144.8 ng/mL). In the current study, we observed that EOC patients with high serum CCL18 levels had obviously poorer overall survival than those with low serum CCL18; the corresponding mean survival times were 25.7 weeks (95% CI, 22.7 to 28.7) and 30.9 weeks (95% CI, 28.2 to 33.5), respectively, ( $P=$ 0.005, Fig. 4). In addition, univariate and multivariate Cox regression analyses showed that FIGO stage and serum CCL18 levels were independent risk factors for the prognosis of EOC patients (Table 4).

Table 4
Univariate and multivariate Cox analysis of variables considered for overall survival rates of ovarian cancer patients

		Univariate			Multivariate
	Category	HR	95% CI	$P$ value	HR	95% CI	$P$ value
Menopausal status	post- vs. pre-	1.128	0.714–1.902	0.347	–	–	–
Primary tumor type	ovary vs. other	0.690	0.293–1.496	0.314	–	–	–
Histological type	serous vs. other	0.793	0.602–1.522	0.352	–	–	–
Grade	3 vs. 1 $+$ 2	2.042	1.144–3.981	0.003	–	–	–
FIGO stage	III $+$ IV vs. I $+$ II	2.456	1.725–3.625	0.001	1.764	1.263–3.465	0.008
Lymph nodes status	positive vs. negative	3.387	1.552–4.254	0.002	1.935	0.693–3.351	0.137
CCL18 (ng/mL)	$\geqslant$ 144.8 vs. $<$ 144.8	2.155	1.288–4.096	0.002	1.941	1.194–3.837	0.006

Abbreviations: HR, hazards ratio; CI, confidence interval; ${}^{*}$ $P$ value $<$ 0.05, statistically significant.

Figure 4.

Kaplan-Meier survival curves of serum CCL18 $\geqslant$ 144.8 ng/mL and $<$ 144.8 ng/mL in patients with EOC.

4. Discussion

In our study, serum CCL18 concentrations were analyzed in 187 patients with EOC, 126 patients with benign PM, and 118 healthy controls; the results demonstrated that CCL18 was significantly overexpressed in PM patients and even higher in patients with ovarian cancer. On the basis of its high expression, the detected expression of CCL18 in patients’ serum can distinguish PM, with PPV and NPV similar to those of CA125. Clinical pathological analysis showed that high expression of CCL18 correlated with EOC stage. Furthermore, high expression of CCL18 also predicted a poor prognosis for ovarian cancer patients; thus, CCL18 could serve as one of the independent prognostic factors for EOC patients.

CCL18 is an easily detected protein by ELISA in serum samples because it is spontaneously secreted by dendritic cells (DCs), monocytes, and macrophages, especially in immature DCs [21]. Thus far, research results have confirmed that CCL18 was upregulated in inflammatory diseases, autoimmune disease, allergic disease, and AIDS (Acquired Immune Deficiency Syndrome) [13, 22]. In accordance with the lymphocyte regulatory functions of CCL18, upregulation of CCL18 was observed in lymphocytic leukemia, which correlated with poor prognoses for patients [23]. Researchers found CCL18 to be upregulated in patients’ serum of several kinds of solid malignancies, and the upregulation of CCL18 also predicted poor prognosis. CCL18 overexpression might because of the immunosuppressive condition of cancer patients caused by the interaction between the host and the tumor. In conclusion, serum CCL18 concentration may serve as an effective biomarker for patients with malignant tumors.

Previous work on CCL18 expression in EOC showed that CCL18 was overexpressed in both the patients’ ascitic fluid and serum [18, 19, 20]. Duluc’s group found that CCL18 expression was significantly downregulated during tumor-associated macrophage (TAMs) activation and participated in antitumor immunity in OC [24]. Not until Song’s group discovered the expression of PITPNM3, a CCL18 receptor, in breast cancer, this chemokine was regarded as an oncogene that stimulates the development of tumor through epithelial-mesenchymal transition (EMT) [25, 26, 27]. After this finding, Wang’s research showed that CCL18 overexpression in EOC tumor tissues correlated with patients’ prognosis because of the promotion of EOC cell metastasis [28]. However, all these studies were restricted to small sample tests, and serum CCL18 was therefore not reported to be powerful enough to be an EOC tumor marker.

On the basis of data from 187 patients with EOC specimens and 126 patients with benign PM, our study confirmed for the first time that serum CCL18 can be appropriately used as a biomarker to diagnose and differentiate EOC from healthy people or even benign PM and, can predict patients’ prognosis. From other researchers’ findings, CCL18 may serve as an even more promising biomarker in EOC and play important roles in tumor progression.

This study has some limitations. Because this is a retrospective study, the level of evidence is not high. Given that the patients were recruited from one center, a multicenter and prospective study focusing on the diagnostic performance and prognostic evaluation of serum CCL18 in patients with EOC is mandatory. Our aim is the clinical application of this serum marker, but much studies need to be done to achieve this aim.

5. Conclusions

The present study demonstrated that the serum level of CCL18 was elevated in patients with EOC compared to patients with benign PM and healthy control subjects, and that serum CCL18 level could be a potential biomarker for EOC, especially for distinguishing between patients with EOC and benign PM. Patients with EOC with higher serum levels of CCL18 had poorer prognoses. These findings imply that serum CCL18 may serve as a potential biomarker for diagnosis and prognostic evaluation in patients with EOC.

Footnotes

Acknowledgments

This work was supported by the Specialized Research Fund for the Science and Technology Department of Guangdong Province (Grant No. 2014A 020212477 to LSL) and the Natural Science Foundation of Guangdong Province, China (Grant Nos. 2015A030313035 to LSL, 2016A030310171 to LJY).

Conflict of interest

No potential conflicts of interest were disclosed.

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Evaluation of serum CCL18 as a potential biomarker for ovarian cancer

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Subjects

Table 1 Clinicopathological variables of the normal controls, benign PMs, and ovarian cancer patients ( n , %)

2.3 Data collection and follow-up

2.4 Statistical analysis

3. Results

3.1 Serum CCL18 levels in patients with EOC, benign PM, and healthy controls

Table 2 The relationship between serum CCL18 levels and clinicopathological variables of the ovarian cancer patients group

Table 3 Diagnosis values of different biomarkers for women with ovarian cancer, benign PMs or normal healthy controls. Positive and negative predictive values (PPV and NPV). CCL18, cutoff value 55.4 ng/mL, CA125, cut off value 35 U/mL

Table 4 Univariate and multivariate Cox analysis of variables considered for overall survival rates of ovarian cancer patients

5. Conclusions

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Clinicopathological variables of the normal controls, benign PMs, and ovarian cancer patients ( $n$ , %)

Table 2
The relationship between serum CCL18 levels and clinicopathological variables of the ovarian cancer patients group

Table 3
Diagnosis values of different biomarkers for women with ovarian cancer, benign PMs or normal healthy controls. Positive and negative predictive values (PPV and NPV). CCL18, cutoff value 55.4 ng/mL, CA125, cut off value 35 U/mL

Table 4
Univariate and multivariate Cox analysis of variables considered for overall survival rates of ovarian cancer patients