Background/Aims: Relevant markers of cancer stem cells (CSCs) may serve as commonly used biomarkers of ovarian cancer (OC). However, their actual clinicopathological and prognostic significance remains inconclusive. Thus, we conducted a meta-analysis to quantitatively evaluate the association between the expression of CSC-relevant markers (ALDH1, CD117, CD133, and CD44) and OC. Methods: We used an odds ratio (OR) and a hazard ratio (HR) with a 95% confidence interval (CI) to estimate the effects by analyzing 52 studies from a literature search. Heterogeneity and sensitivity were evaluated, as well. Publication bias was assessed using funnel plots and Egger tests. Results: ALDH1 expression was statistically associated with FIGO stage (OR=1.872, 95%CI=1.14-3.076, P=0.013) and lymph invasion (OR=2.78, 95%CI=1.08-7.152, P=0.034). CD117 expression was significantly associated with FIGO stage (OR=2.01, 95%CI=1.35-2.98, P=0.001). CD133 expression was correlated with FIGO stage (OR=3.410, 95%CI=2.196-5.294, P< 0.001) and differentiation grade (OR=2.672, 95%CI=1.354-5.272, P=0.005). CD44s was related to chemotherapy resistance (OR=3.218, 95%CI=1.148-9.016, P=0.026). Furthermore, overexpression of ALDH1 (HR=1.494, 95%CI=1.207-1.849, P< 0.001), CD117 (HR=1.395, 95%CI=1.025-1.898, P=0.034) or CD44s (HR=1.725, 95%CI=1.135-2.623, P=0.011) was associated with poor OS. Further, overexpression of both ALDH1 (HR=1.524, 95%CI=1.158-2.007, P=0.003) and CD44s (HR=2.12, 95%CI=1.692-2.657, P< 0.001) was correlated with worse DFS. Conclusion: CSC markers are useful predictive or prognostic biomarkers for OC in clinical assessments. Combined detection of CSC marker expression may be a powerful tool for prognostic predictions in clinical practice for patients with OC.

Ovarian cancer (OC) is the fifth leading cause of cancer deaths in women and the most lethal gynecological malignancy [1]. Although most OC patients initially exhibit a sensitive response to platinum-based chemotherapy, the overall survival (OS) of patients with OC is relatively low because 70% of patients are diagnosed with an advanced stage of OC and will ultimately succumb to chemo-resistant disease [2-4]. More seriously, the five-year survival rate of OS remains poor [2]. Therefore, there is a great need for identification of molecular biological prognostic markers to predict patient outcomes, which could also be beneficial in developing strategies and improving survival rates for OC.

Cancer stem cells (CSCs) are a distinct subpopulation of cancer cells characterized by their ability to generate heterogeneity and sustain tumor self-renewal [5-7]. Recently, accumulated evidence has identified CSCs as a pivotal players in OC progression and prognosis [8-10]. Several stem cell markers have been described for OC, including CD44, CD133, ALDH1, CD117, CD24, BMP and EpCAM [11-16]. Furthermore, it has been reported that CSC markers, such as ALDH1, CD117, CD133 and CD44, may serve as valuable prognostic indicators for OC [17-20]. However, due to the diversity of research methods employed, differences in cut-off value, study sample size, and variance in race, the prognostic value of ALDH1, CD117, CD133 and CD44 expression in OC remains controversial [18, 21-27].

No study has compared the relationship between these 4 common CSC markers and OC, including clinicopathological features of the disease, and the effect of the markers on survival. Therefore, we collected the available literature and conducted this meta-analysis to determine whether ALDH1, CD117, CD133 or CD44 overexpression would correlate with OC clinicopathology and prognosis and to explain which of these markers would have more clinical value based on meta-analysis evidence.

Literature search strategy

Literature searches without any linguistic limitations were conducted up to May 3, 2017, in the following electronic databases: PubMed and Web of Science. The search strategy included the following words and phrases: (“Aldehyde Dehydrogenase” or “ALDH”) and (“Ovarian Neoplasm,” “Ovarian Carcinoma,” “Ovarian Cancer,” and “Ovarian Tumor”); (“CD117,” “c-kit” or “tyrosine-protein kinase Kit”) and (“Ovarian Neoplasm,” “Ovarian Carcinoma,” “Ovarian Cancer,” and “Ovarian Tumor”); (“CD133,” “Prom-1” or “AC133”) and (“Ovarian Neoplasm,”“Ovarian Carcinoma,” “Ovarian Cancer,” and “Ovarian Tumor”); and (“CD44”) and (“Ovarian Neoplasm,” “Ovarian Carcinoma,” “Ovarian Cancer” and “Ovarian Tumor”). Additionally, the reference lists of relevant articles were screened to identify additional relevant studies.

Study selection

Two reviewers (Yifeng Tao and Meiqin Li) selected the eligible studies independently, and disagreements were resolved by discussion. The eligible studies for this meta-analysis had to meet the following inclusion criteria: 1) the expression of OC CSC-relevant markers (ALDH1, CD117, CD133 and CD44) was detected in cancer tissue rather than in the serum or any other kinds of specimens; 2) the expression of these markers was detected using an immunohistochemistry (IHC) method; 3) the relationship between the expression of these markers and clinicopathological characteristics of OC was evaluated; 4) the expression of these markers with OS/disease-free survival (DFS) for OC was reported; and 5) HRs and 95% CIs were provided in the text, or sufficient data was provided for the calculation of HRs and 95% Cis. Non-research articles, studies that were focused on animal or human cell lines, or papers lacking information on OC prognosis were excluded.

In addition, due to a lack of adequate information for CD44v3, CD44v7-8, CD44v9, and CD44v10, we analyzed only two CD44 isoforms, namely, CD44s and CD44v6.

Data extraction

Two investigators (Rongyong Huang and Meiqin Li) carried out the data extraction independently, and disagreements were resolved by a 3rd party (Yifeng Tao). The following information was extracted: first author’s surname, year of publication, country of origin, sample size, cut-off values forALDH1/CD117/ CD133/CD44, FIGO stage, and survival data.

Qualitative assessment

The quality of each of the eligible studies was assessed independently by 2 investigators using the Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort studies. Briefly, the scale uses a star system to indicate the quality of each study. Studies that receive a score of ≥7 stars are considered to be of high quality.

Statistical Analysis

The odds ratio (OR) and 95% confidence interval (CI) were used to assess the correlation between the expression of these OC CSC markers and clinicopathological parameters, including FIGO stage (III/IV versus I/II), tumor differentiation grade (poor versus well/moderate), lymph nodal metastasis (positive versus negative), pathological type (serous type versus other type) and response to chemotherapy (resistant versus sensitive). In the present study, an OR> 1 indicated a higher probability of tumor progression in OC patients overexpressing these CSC markers. Hazard ratios (HR) were used as a summary statistic for survival outcomes, as described by Parmar et al. An HR greater than 1 represented poor prognosis in OC. Heterogeneity among primary studies was assessed with the Q-test and the I2 statistic. A Q test P value < 0.10 and/or an I2 statistic > 50% indicated significant heterogeneity between studies, and we used the random effects model to calculate the pooled OR/HR and 95% CI [28]. Otherwise, the fixed effects model was used [29]. Begg’s funnel plots were used to evaluate publication bias. Sensitivity analysis was introduced to evaluate the influence of a single study on the overall estimate. All statistical analyses were performed using Stata 12.0 statistical software (Stata Corporation, College Station, TX, USA). A two-tailed P < 0.05 was considered to be statistically significant.

Study characteristics

The literature selection process for choosing eligible studies is shown in Fig. 1. In accordance with the inclusion criteria, a total of 52 articles were eligible for the meta-analysis [13, 17-27, 30-69]. The basic characteristics of each eligible study are summarized in Table 1. The eligible studies were published between 1997 and 2017. The sample sizes of the included studies ranged from 11 to 440. Among these studies, 15 studies involved patients with ALDH1 [19, 22, 26, 30-41], 8 studies involved patients with CD133 [18, 23, 25, 30, 31, 37, 42, 43], 25 studies involved patients with CD44 [17, 21, 24, 44-64, 66], 7 studies involved patients with CD117 [13, 20, 26, 27, 67-69], 3 studies involved patients with ALDH1 and CD133 [30, 31, 37], and 1 study involved patients with ALDH1 and CD117 [26]. According to the NOS quality assessment, 52 of the studies were categorized as high quality.

Table 1.

Association between CSCs expression and ovarian cancer prognosis. Abbreviations: OS, overall survival; DFS, disease-free survival; Pbias, the p-value of Egger linear regression test for evaluating publication bias

Association between CSCs expression and ovarian cancer prognosis. Abbreviations: OS, overall survival; DFS, disease-free survival; Pbias, the p-value of Egger linear regression test for evaluating publication bias
Association between CSCs expression and ovarian cancer prognosis. Abbreviations: OS, overall survival; DFS, disease-free survival; Pbias, the p-value of Egger linear regression test for evaluating publication bias
Fig. 1.

The flowchart of the study selection process.

Fig. 1.

The flowchart of the study selection process.

Close modal

Correlation of ALDH1/CD117/CD133 /CD44 with clinicopathological features of OC patients

Table 2 shows the results for correlation between ALDH1/CD117/CD133/CD44 and the clinicopathological parameters. Overall analyses demonstrated that ALDH1 expression was statistically associated with FIGO stage (OR=1.872, 95% CI = 1.14-3.076, P=0.013) and lymph invasion (OR=2.78, 95% CI = 1.08-7.152, P=0.034) (Fig. 2A-B). CD117 expression was significantly associated with FIGO stage (OR=2.01, 95%CI=1.35-2.98, P=0.001) (Fig. 2E). CD133 expression was correlated with FIGO stage (OR=3.41, 95%CI=2.196-5.294, P<0.001), which was consistent with the results for ALDH1 (Fig. 2C). Moreover, CD133 expression was statistically associated with differentiation grade (OR=2.672, 95%CI=1.354-5.272, P=0.005) (Fig. 2D), suggesting that CD133 might be involved in the malignant progression of OC. It is worth noting that overexpression of CD44s is associated with chemotherapy resistance (OR=3.218, 95%CI=1.148-9.016, P=0.026) (Fig. 2F), indicating that high CD44s expression possibly contributes to a high risk of chemotherapy resistance in OC patients. However, no clear correlation was found between CD44s/CD44v6 expression and FIGO stage, lymph invasion, differentiation grade, and pathological type (all P> 0.05).

Table 2.

Overall analysis of CSCs expression association with clinical features. Abbreviations: Pbias, the p-value of Egger linear regression test for evaluating publication bias

Overall analysis of CSCs expression association with clinical features. Abbreviations: Pbias, the p-value of Egger linear regression test for evaluating publication bias
Overall analysis of CSCs expression association with clinical features. Abbreviations: Pbias, the p-value of Egger linear regression test for evaluating publication bias
Fig. 2.

Association of CSCs expression with clinical features.(A-B) association of ALDH1 expression with FIGO stage (A) and lymph invasion (B); (C-D) association of CD133 expression with FIGO stage (C) and differentiation grade (D); (E) association of CD117 expression with FIGO stage; (F) association of CD44s expression with chemotherapy resistant.

Fig. 2.

Association of CSCs expression with clinical features.(A-B) association of ALDH1 expression with FIGO stage (A) and lymph invasion (B); (C-D) association of CD133 expression with FIGO stage (C) and differentiation grade (D); (E) association of CD117 expression with FIGO stage; (F) association of CD44s expression with chemotherapy resistant.

Close modal

Impact of ALDH1/CD117/CD133/CD44 expression on survival of OC patients

To further investigate the relationship between ALDH1/CD117/CD133/CD44 and the prognosis of OC patients, survival analysis of the HR for OS and DFS was conducted. The results are shown in Fig. 3 and Table 3.

Table 3.

Association between CSCs expression and ovarian cancer prognosis. Abbreviations: OS, overall survival; DFS, disease-free survival; Pbias, the p-value of Egger linear regression test for evaluating publication bias

Association between CSCs expression and ovarian cancer prognosis. Abbreviations: OS, overall survival; DFS, disease-free survival; Pbias, the p-value of Egger linear regression test for evaluating publication bias
Association between CSCs expression and ovarian cancer prognosis. Abbreviations: OS, overall survival; DFS, disease-free survival; Pbias, the p-value of Egger linear regression test for evaluating publication bias
Fig. 3.

Association between CSCs expression and ovarian cancer prognosis. (A-B) association of ALDH1 expression with overall survival (A) and disease-free survival (B); (C-D) association of CD44s expression with overall survival (C) and disease-free survival (D).

Fig. 3.

Association between CSCs expression and ovarian cancer prognosis. (A-B) association of ALDH1 expression with overall survival (A) and disease-free survival (B); (C-D) association of CD44s expression with overall survival (C) and disease-free survival (D).

Close modal

The data for this analysis indicated that overexpression of ALDH1 (HR=1.494, 95%CI=1.207–1.849, P<0.001), CD117 (HR=1.395, 95%CI=1.025-1.898, P=0.034) or CD44s (HR=1.725, 95%CI=1.135-2.623, P=0.011) is associated with poor OS (Fig. 3A, C). Furthermore, overexpression of both ALDH1 (HR=1.524, 95% CI = 1.158-2.007, P=0.003) and CD44s (HR=2.12, 95%CI=1.692-2.657, P<0.001) is correlated with worse DFS (Fig. 3B, D). However, data analysis showed that there is no significant relationship between the overexpression of CD117 or CD133 and DFS. Additionally, a relationship between CD44v6 overexpression and poor OS rate was not found, and there was lack of sufficient information to study the relationship between CD44v6 expression and DFS.

Sensitivity analysis and Publication Bias

Sensitivity analysis indicated that most studies did not substantially influence the pooled OR/HR, except for the results related to OS and CD44v6 expression. Publication bias analysis of the studies indicated there was no obvious publication bias in most studies, except for the results related to OS and ALDH1 expression, which suggests that a publication bias possibly existed for OS results (Table 2).

Whereas advanced ovarian cancer is generally responsive to conventional combinations of primary cytoreductive surgery and paclitaxel-platinum chemotherapy initially, most ovarian cancer patients will inevitably relapse with metastasis, recurrence, and drug resistance [2, 3]. Although deadly, ovarian cancer is one of the more chemosensitive solid malignancies. One model by which to explore ovarian cancer tumor heterogeneity is the cancer stem cell hypothesis. This idea proposes that within a heterogeneous ovarian tumor, there are small cell populations with increased tumorigenicity and differentiating capacity compared to other tumor cells that are responsible for ovarian tumor initiation, recurrence, and metastasis [70, 71].

The clinical significance of the most frequently used CSC markers OC, ALDH1, CD117, CD133 and CD44 remains contradictory and inconclusive. Based on these controversial studies, a meta-analysis was conducted to evaluate the precise impact of ALDH1, CD117, CD133 and CD44 on the clinicopathological features and prognosis of OC.

ALDH1 plays a role in retinoic acid formation by oxidizing the all-trans-retinal and 9-cisretinal involved in retinoid signaling, which has been linked to the stemness of CSCs [72, 73]. Moreover, ALDH1 plays a key role in the maintenance of ovarian cancer stem cell-like properties and might mediate carboplatin resistance by altering regulation of the cell cycle and DNA repair networks [72].

CD117 (c-kit), a well-known proto-oncoprotein, is normally activated by binding to its ligand (stem cell factor), which activates cell-signaling cascades that are important in the regulation of cell proliferation, apoptosis, adhesion, and differentiation [74, 75].

CD133, a pentaspan membrane glycoprotein, has been identified as a CSC marker for various cancers. The biological function of CD133 remains unclear, but it may be involved in primitive cell differentiation and epithelial-mesenchymal interactions [76].

CD44 is a receptor for the extracellular matrix component hyaluronic acid and other extracellular matrix components that enable CSCs to sense environmental changes and mediate signal transduction to regulate CSC stemness properties [77]. CD44-hyaluronan complex activates Nanog, an embryonic stem cell transcription factor important in regulating CSC survival, self-renewal, maintenance, and chemoresistance [78].

Our results indicate that positive ALDH1, CD117, CD133 and CD44s expression can effectively predict several clinicopathological features and poor outcomes in patients with OC. Because the related features do not overlap, combined detection of ALDH1, CD117, CD133 and CD44s expression may be an especially effective tool for diagnosis of patients with OC. However, because publication bias was observed in the pooled HR for the OS and DFS of ALDH1 expression, our results should be cautiously interpreted.

Several potential limitations should be taken into consideration and additional results should also be interpreted cautiously. First, diverse antibody clones and antibody concentrations were used in detecting ALDH1, CD117, CD133 and CD44 expression, which could cause inconsistent results. Second, lack of a universal standard for defining high and low expression of CSC markers may impact the results of this meta-analysis. Third, relatively large heterogeneity was found in the majority of the analyses. Fourth, expression of these markers was detected using an IHC method, which suffers from severe limitations as no functional test, non-quantitative and non-canonical analysis. Fifth, we evaluated and calculated the HRs via survival curves, which might reduce the reliability of the results. Finally, publication bias was observed in the pooled HR for the OS and DFS of ALDH1 expression, thus potentially inflating the estimate for the association of CSCs with poor prognosis. Despite these limitations, we have provided a comprehensive analysis of the association between CSC markers and the clinicopathology and prognosis of OC patients.

In conclusion, our meta-analysis revealed the value of ALDH1, CD133 and CD44s as 3 significant clinical indicators for patients with OC. ALDH1 overexpression was related to FIGO stage and lymph invasion. CD133 overexpression was significantly correlated with FIGO stage and tumor differentiation grade. CD44s overexpression was associated with chemotherapy resistance. Moreover, ALDH1, CD117, CD133 and CD44s were associated with worse prognosis. Combined detection of ALDH1, CD117, CD133 and CD44s expression may be a powerful tool in clinical practice for predicting prognosis of patients with OC. However, because of certain limitations, further well-designed studies with large samples, standard cohorts, and long-term follow-up are required for confirmation.

This work was supported by grants from National Science Foundation of China (8176110049), National Science Foundation of Guangxi (2017GXNSFBA1980047), the Bureau of Public Health of Guangxi Province(Z2015624) and the Natural Science Foundation of Guangxi Medical University Programs (GXMUYSF201630).

Yifeng Tao, Meiqin Li and conceived and designed the experiments; Min Fang, Hui Li, Dan Mo and Tian Zeng analyzed data, Yifeng Tao, Hui Li, Min Fang, Rongyong Huang and Meiqin Li wrote the manuscript. All authors reviewed and approved the manuscript.

No conflict of interests exists.

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Y. Tao, H. Li and R. Huang contributed equally to this work.

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