|Year : 2015 | Volume
| Issue : 2 | Page : 375-380
Clinical significance of plasma lysophosphatidic acid levels in the differential diagnosis of ovarian cancer
Yun-Jie Zhang, Li-Yan Cao, Zhan-Zhao Fu, Yan-Jie Wang, Guang-Xia Wang, Tao Gu
Department of Radiation Oncology Division, The First Hospital of Qinhuangdao City, Qinhuangdao, China
|Date of Web Publication||7-Jul-2015|
Department of Radiation Oncology Division, The First Hospital of Qinhuangdao City, Cultural Road No. 258, Qinhuangdao-066 000
Source of Support: None, Conflict of Interest: None
Objective: To investigate the value of lysophosphatidic acid (LPA) in the diagnosis of ovarian cancer.
Materials and Methods: We first performed a hospital-based, case-control study involving 123 ovarian cancer patients and 101 benign ovarian tumor patients, and then conducted a meta-analysis with 19 case-control studies to assess the correlation between ovarian cancer and plasma LPA levels.
Results: The case-control study results demonstrated that ovarian cancer patients have increased LPA and cancer antigen (CA)-125 levels compared to patients with benign ovarian tumor (LPA: Ovarian cancer vs benign ovarian tumor: 5.28 ± 1.52 vs 1.82 ± 0.77 μmol/L; CA-125: Ovarian cancer vs benign ovarian tumor: 87.17 ± 45.81 vs. 14.03 ± 10.14 U/mL), which showed statistically significant differences (both P < 0.05). LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis excelled CA-125 in the diagnosis of ovarian cancer (both P < 0.05). The areas under the receiver operating characteristic (ROC) curve in the diagnosis of ovarian cancer (LPA: 0.983; CA-125: 0.910) were statistically significant compared with the reference (both P < 0.001) and the difference of the areas of ROC curve between LPA and CA-125 in the diagnosis of ovarian cancer showed statistically significant difference (P < 0.05). The meta-analysis results suggested that plasma LPA levels were higher in ovarian cancer tissues than in benign tissues (standardized mean difference (SMD) =2.36, 95% confidence interval (CI): 1.61-3.11, P < 0.001) and normal tissues (SMD = 2.32, 95% CI: 1.77-2.87, P < 0.001).
Conclusion: LPA shows greater value in the diagnosis of ovarian cancer compared to CA-125 and may be employed as a biological index to diagnose ovarian cancer.
Keywords: Benign ovarian tumor, bioactive phospholipid, CA-125, diagnosis, endothelial differentiation gene, G protein-coupled receptors, lysophosphatidic acid, ovarian cancer, sensitivity, specificity
|How to cite this article:|
Zhang YJ, Cao LY, Fu ZZ, Wang YJ, Wang GX, Gu T. Clinical significance of plasma lysophosphatidic acid levels in the differential diagnosis of ovarian cancer. J Can Res Ther 2015;11:375-80
|How to cite this URL:|
Zhang YJ, Cao LY, Fu ZZ, Wang YJ, Wang GX, Gu T. Clinical significance of plasma lysophosphatidic acid levels in the differential diagnosis of ovarian cancer. J Can Res Ther [serial online] 2015 [cited 2020 May 31];11:375-80. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/375/157335
| > Introduction|| |
Ovarian cancer is the second most common lethal cancer among gynecologic tumors originally in that the highly metastatic cells slough from primary tumors and subsequently spread throughout the peritoneal cavity.  Ovarian cancer represents the fifth leading causes of malignancy-related mortality among women in the United States with approximate 15,000 deaths each year. , The risk of ovarian cancer enhances in individuals who have greater lifetime ovulations, and thus those who have never had children are at high risk.  Besides, low parity, early age of menarche, late age of menopause, excessive gonadotropin secretion, transportation of carcinogens, and lifestyle (smoking or obesity) appears to be involved with the onset and development of ovarian cancer. , Due to lack of specific symptoms presented by ovarian cancer and no screening techniques recommended to diagnose preinvasive or early-stage disease, more than 70% of patients are diagnosed at advanced stage and the prognosis in advanced-stage ovarian cancer remains poor with a 5-year survival rate of less than 30%. , Currently, cancer antigen (CA)-125 has been still extensively used to diagnose ovarian cancer, while it does not show great value in the diagnosis of ovarian cancer with relatively dissatisfactory sensitivity and specificity. 
Lysophosphatidic acid (LPA) is a water-soluble phospholipid that comprises a phosphate, a glycerol, and a fatty acid and can be served as a potent signaling molecule. , LPA in blood is produced from extracellular lysophosphatidylcholine by a secreted lysophospholipase D, called autotaxin, primarily isolated as an "autocrine motility factor" for tumor cells.  To date, at least six specific G protein-coupled receptors have been identified, termed LPA receptor-1 (LPA1), LPA2, LPA3, LPA4, LPA5, and LPA6, which mediate both distinct and overlapping signaling pathways. , Through the binding of G protein-coupled LPA receptors, LPA facilitates a wide range of biological functions, such as cell proliferation, differentiation, migration, cytoskeleton reorganization, cytokine production, platelet aggregation, morphogenesis changes, and cell survival both normal and malignant.  Under normal circumstances, LPA in the body fluids and bloodstream is at submicromolar concentrations or lower; but in ascites fluid of ovarian cancer patients, it seems to have higher concentrations. 
Many studies have assessed the correlation between LPA and ovarian cancer. ,,,,,,,,,,,,,,,,,, Nevertheless, the results from these underpowered studies have failed to clearly and reliably resolve this question. Therefore, we have performed a new case-control study with larger sample size to investigate LPA and ovarian cancer, and then combined our results with a meta-analysis of related studies to obtain a more definitive and precise estimate of LPA-ovarian cancer correlation.
| > Materials and methods|| |
The study was approved by the Ethics Committee of the Second Hospital of Jilin University, China. All eligible patients signed a document of informed consent, and this study was performed based on the Declaration of Helsinki. 
This cases-control study enrolled 123 ovarian cancer patients aged 29-65 years (median age 55 years) and 101 benign ovarian tumor patients aged 28-66 years (median age 54 years) between January 2013 and September 2014 form the first hospital of Qinhuangdao City. The pathological types are: Serous cystadenocarcinoma (n = 66), mucinous cystadenocarcinoma (n = 16), and endometrioid carcinoma (n = 13). Pathological staging based on the International Federation of Gynecology and Obstetrics (FIGO) in 2014:  Fourteen in stage I, 16 in stage II, 62 in stage III, and eight in stage IV. All subjects were undertaken pathological diagnosis and patients with other gynecologic tumors, pelvic inflammatory disease, vascular occlusive diseases, hypertension, and diabetes mellitus were excluded.
Determination of LPA and CA-125 levels
All subjects with empty stomachs were peripherally phlebotomized at 6 ml, which was anticoagulated by the anticoagulant (No. 1; Beijing Taifushi Technical Developing Company) present in the LPA kit for the determination of LPA and CA-125. After centrifugation at 8,000 rpm for 10 min, the supernatant (1 ml) was absorbed, sample was extracted for phospholipid, chromogenic agent was added and kept in water bath at 90°C for 5 min, and then maintained at room temperature for 35 min. The semiautomatic biochemical analyzer (BG2000B) was used for colorimetry and absorbance (A) at the wavelength of 636mm (LPA = 30 × ((A sample - A control )/(A sample - A control ))). All subjects in two groups with empty stomachs were peripherally phlebotomized at 3 ml again in which CA-125 was determined by radioimmunoassay. The critical values of normal plasma LPA and CA-125 levels are 1.3 μmol/L and 35 U/mL, respectively. ,
Statistical Package for Social Sciences (SPSS) 20.0 was employed for our statistical analysis. Continuous data were exhibited by standard deviation ± mean using t-test for further examination; while categorical data were presented with percentage using Chi-square test. P < 0.05 was defined as significant.
An electronic search was undertaken in the following databases: PubMed, Wanfang, China National Knowledge Infrastructure (CNKI), and VIP (updated on May 30 th , 2014) for published papers investigating the correlation of plasma LPA levels with ovarian cancer, utilizing relevant keywords ("lysophosphatidic acid" or "MOPA" or "LPA" or "1-oleoyl-lysophosphatidic acid" or "monooleylphosphatidate" or "1-O-oleyllysophosphatidic acid") and ("ovarian tumors" or "ovary tumors" or "ovary cancers" or "ovarian cancer" or "cancer of ovary" or "ovarian carcinoma" or "ovarian adenocarcinoma" or "ovarian tumor" or "EOC"). Our meta-analysis enrolled human-associated case-control studies that focused on the diagnostic value of plasma LPA levels in ovarian cancer. Subsequently, we excluded abstract, summary, duplicates, or studies without control population. During the process of statistical analysis, the summary standardized mean differences (SMDs) with 95% confidence interval (CI) were calculated to provide quantitative evidence of all included studies by a random-effects model or a fixed-effects model.  A random-effect model was employed when the heterogeneity exists among studies; otherwise a fixed-effect model was applied. The Cochran's Q-statistic (P < 0.05 was defined as statistically significant) was available for the evaluation of the heterogeneity  which was further examined by I2 test (0 ~ 100%: No heterogeneity ~ maximal heterogeneity). 
| > Results|| |
Plasma LPA and CA-125 levels
As shown in [Table 1] and [Figure 1], both plasma LPA and CA-125 levels were higher in ovarian cancer group than benign ovarian tumor group (LPA: Ovarian cancer group: (5.28 ± 1.52) μmol/L; benign ovarian tumor group: (1.82 ± 0.77) μmol/L; CA-125: ovarian cancer group: (87.17 ± 45.81) U/mL; and benign ovarian tumor group: (14.03 ± 10.14) U/mL), which showed statistically significant differences (both P < 0.05).
|Figure 1: Comparison of plasma lysophosphatidic acid (LPA) and cancer antigen (CA)-125 levels in ovarian cancer group (OC) and benign ovarian tumor (BOT) group|
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|Table 1: The comparison of the plasma lysophosphatidic acid and cancer antigen 125 levels in ovarian cancer group and benign ovarian neoplasm|
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Diagnostic value of plasma LPA and CA-125
In [Table 2], pathological results were used as golden standard and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis of plasma LPA in diagnosing ovarian cancer were 93.33, 89.42, 91.06, 89.42, and 91.52%, respectively; while serum CA-125 were 84.91, 72.65, 73.77, 72.65, and 78.48%, respectively. Thus, LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis excelled CA-125 in the diagnosis of ovarian cancer (both P < 0.05).
|Table 2: The comparison of the plasma lysophosphatidic acid and CA125 levels about sensitivity, specificity, positive predictive value, negative predictive value and accuracy rate of diagnosis|
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Accuracy rate of diagnosis of LPA and CA-125
As shown in [Table 3], the areas under the receiver operating characteristic (ROC) curve in the diagnosis of ovarian cancer (LPA: 0.983; 95% CI: 0.970-0.995; CA-125: 0.910; 95% CI: 0.872-0.948) were statistically significant compared with the reference (both P < 0.001); and the difference of the areas under the ROC curve between LPA and CA-125 in the diagnosis of ovarian cancer showed statistically significant difference (P < 0.05), indicating that LPA with advanced diagnostic value was better than CA-125 in ovarian cancer. The ROC curves of LPA and CA-125 (nonparametric tests of Hanley-McNeil) in the diagnosis of ovarian cancer are shown in [Figure 2].
|Figure 2: Receiver operating characteristic (ROC) curve about plasma LPA and CA-125 in the diagnosis of ovarian cancer|
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|Table 3: The receiver operating characteristic curve about the plasma lysophosphatidic acid and CA125 in the diagnosis of ovarian cancer|
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A total of 19 case-control studies published between 1996 and 2013 met our selection criteria and enrolled into our final meta-analysis. ,,,,,,,,,,,,,,,,,, Sixteen studies were performed on Asians (China (n = 15) and[TAG:2][/TAG:2]
Turkey (n = 1)), and the rest three studies on Caucasians (Slovenia (n = 1) and USA (n = 2)). These 19 studies included a total of 2,520 subjects (980 ovarian cancer cases, 872 benign ovarian tumor cases, and 668 healthy controls). Plasma LPA levels in patients and controls were determined by enzyme-linked immunosorbent assay (ELISA; n = 13), bioassay (n = 4), phosphorus determination (n = 1), and inorganic phosphorus (n = 1). As shown in [Figure 3], plasma LPA levels were higher in cancer tissues than in benign tissues (SMD = 2.36, 95% CI: 1.61-3.11, P < 0.001) and normal tissues (SMD = 2.32, 95% CI: 1.77-2.87, P < 0.001).
|Figure 3: Comparison of pooled standardized mean differences (SMDs) for LPA levels in cancer tissues, benign tissues, and normal tissues. (a) Cancer tissue vs benign tissue and (b) cancer tissue vs normal tissue|
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| > Discussion|| |
Ovarian cancer has the poorest prognosis among all gynecologic malignancies due to lack of an inability to diagnose ovarian cancer at an early and curable stage, and there has been no significant increase in cure rates during the past 30 years.  In the present study, we conducted a case-control report with a meta-analysis using CA-125 as the reference to confirm the correlation between LPA and ovarian cancer. This study demonstrated that LPA showed great value in the diagnosis of ovarian cancer and may be served as a biological index to diagnose ovarian cancer. Ovarian cancer cells can generate LPA by mesothelial cells, forming an autocrine loop mediating growth, survival as well as motility of tumor cells and increasing invasion and metastasis. , In our study, both case-control study and meta-analysis including 19 reports provided evidence that the LPA levels were notably higher in ovarian cancer tissues when compared to benign ovarian tumor tissues and normal tissues. Shen et al., also found that plasma LPA levels were quite low in healthy individuals and did not apparently increase in leukemia or breast cancer, while ovarian cancer patients has significantly elevated plasma LPA levels. 
Furthermore, the differential diagnosis of ovarian cancer depended on the degree of tumor cell invasion and metastasis by the surrounding microenvironment where invasiveness and infiltration was mediated by the coordinated interaction among growth factors, chemokines, proteases, and various cytokines generated from either tumor cells or normal cells.  LPA, at pathological concentrations, can mediate tumor neovascularization, invasion along with metastases, and worsen the prognosis in ovarian malignancies.  Through the activation of VEGF's role and its receptor expression of VEGFR-2, LPA plays a part in VEGF and VEGFR-2 complex and modulates the LPA-induced signaling axis, resulting in cell proliferation, migration, and the development of angiogenesis in ovarian cancer, which mediates tumor progression with advanced stage and poor prognosis of ovarian cancer patients.  Besides, LPA receptors is provoked to make their effects via the induction of LPA expression, and by LPA2 and LPA3, LPA can upregulate the expression of several angiogenic factors, such as interleukin-6 (IL-6) and IL-8, thus promoting the growth and metastasis of tumor.  At the same time, the aberrant production of LPA receptors were considered to excessively act in ovarian cancer patients by stimulating and regulating MMPs secretion, influencing ovarian cancer tumor growth and migration mechanism.  In our study, the sensitivity and specificity of plasma LPA used for the diagnosis of ovarian cancer is 93.33 and 84.91%, respectively, both of which were greater compared with serum CA-125. Consistent with our results, Bese et al., reported that LPA with higher sensitivity and specificity can be a more valuable biomarker to detect ovarian cancer pathophysiologic features compared to CA-125. 
In summary, our study demonstrated that LPA with advanced sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of diagnosis shows greater value in the diagnosis of ovarian cancer compared to CA-125 and may be employed as a biological index to diagnose ovarian cancer, and the regulation of plasma LPA levels may be a promising target for genetic therapy of ovarian cancer.
| > Acknowledgments|| |
We would like to appreciate the reviewers for their helpful comments on this paper.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]