Background
Ovarian cancer is one of the common gynecological malignancies featured by several symptoms (including bloating, pelvic pain, abdominal swelling as well as loss of appetite) [
1‐
4]. It has been reported to be the seventh frequently diagnosed cancer and the fourth commonest causes of cancer-related death [
1‐
4]. According to statistical reports, ovarian cancer occurs approximately 239,000 new cases as well as causes estimated 151,900 deaths worldwide in 2012, and happens nearly 52,100 new cases as well as results in 22,500 deaths in China during 2015 [
1‐
4]. Owning to obscure symptoms at an early stage, fast progression, wide metastasis and high recurrence, the prognosis of ovarian cancer patients is far less satisfaction although improvement has been achieved in the disease management (such as imaging, histopathology, surgery as well as chemotherapy) [
1]. Hence, further exploration related to additional and convincing biomarkers is imperative to supervise tumor progression for the promotion of prognosis in ovarian cancer patients.
Cancer stem cells (CSCs) are considered as a small class of tumor cells mass with self-renewing capacity, heterogeneity as well as resistance to chemotherapy/ radiotherapy, which play critical roles in tumor initiation, progression and maintenance [
5,
6]. As one of the most common markers of CSCs, aldehyde dehydrogenase (ALDH) involves in the tumor development and progression processes of various carcinomas, including breast cancer, colorectal cancer, prostate cancer as well as bladder cancer [
7‐
10]. Also, there are several clinical trials investigating the correlation of ALDH expression with the prognosis in ovarian cancer patients, whereas controversial results still existed [
11‐
13]. Regarding that these controversial results might be caused by relatively small sample size, different inclusion criteria, outcomes assessed measures or other factors in different clinical studies, the comprehensive meta-analyses are needed. Although there is one previous meta-analysis including 1258 ovarian cancer patients from 7 studies (6 articles) in 2013, the number of included patients and studies is still relatively small [
14]. Thus we performed additional comprehensive meta-analysis including 14 studies (13 articles) with 2210 ovarian cancer patients, and the purpose was to assess the association of ALDH expression with overall survival (OS) and disease-free survival (DFS)/ progression-free survival (PFS) in ovarian cancer patients.
Discussion
Malignant tumor has been identified to be consisted of a heterogeneous population of cells, among which, CSCs are a small group of cells presenting with high tumor-initiating potential, which devote into high tumor recurrence and worse distant metastasis in patients with various carcinomas, implying that the elimination of CSCs is essential for improvement of prognosis in these cancer patients [
11]. In order to distinguish CSCs from a larger number of cancer cells, there are different methods including utilization of markers in cells surface (such as CD44, CD 90 or CD133), side population (SP) assay as well as ALDEFLUOR assay related to ALDH1 enzyme activity [
23‐
26].
As a common marker of CSCs, ALDH possesses the responsibility to catalyze the oxidation of aldehyde, subsequently contributing to cellular homeostasis, which has been identified to be related to the function as stem cells such as self-renewal capability and stress-resistant properties [
7,
25]. Although upregulation of most CSCs markers plays an important role in worse prognosis in cancer patients, several contradictions still exist on the putative CSC-marker ALDH expression in published studies. In order to clarify this problem, only one previous meta-analysis has examined the influence of ALDH on the survival of ovarian cancer patients and discloses that elevated ALDH expression is an independent risk factor for prognosis in ovarian cancer patients [
14]. However, that previous meta-analysis just includes 7 studies (6 articles) with a total of 1258 ovarian cancer patients and is published in 2013, whose sample size is relatively small and the published time is relatively early. Therefore, in this comprehensive meta-analysis, we analysed 14 studies (13 articles) with 2210 ovarian cancer patients, among these, 6 studies revealed that high expression of ALDH was associated with poor OS, 4 studies concluded that ALDH expression was positively correlated with DFS/PFS, and Deng et al. showed ALDH was unfavorable factors on both OS and DFS/PFS in ovarian cancer patients [
12,
27‐
34]. However, there were 4 studies that support no association of ALDH with the survival of ovarian cancer [
7,
35‐
37].
In addition, subgroup analysis by different cut-off class also presented with several interesting discovers, which showed correlation of high ALDH expression with poor OS and DFS/PFS when studies set the cut off class as low expression, but not high expression in ovarian cancer patients, which implied that ALDH expression existed in a small subpopulation of cancer cells, and we guessed when the cut-off class is defined as high expression of ALDH, most of ovarian cancer patients with intermediate ALDH expression are excluded and assigned to low expression group.
In this meta-analysis, We performed funnel plot and sensitivity analysis to assess publication bias and the stability of the crude results, and we discovered no evidence of publication bias in OS as well as DFS/PFS of patients with ovarian cancer, and pooled HR of OS as well as DFS/PFS was not impacted by the exclusion of any single study, although omitting Chang 2009 had a numerically great influence on IRS compared to omitting other studies, thus, the conclusion was stable. However, further menta-analysis including new relevant studies is greatly needed for validation.
The underlying mechanism of the correlation between evaluated ALDH expression and worse prognosis in ovarian cancer is still unclear. However, there are several relevant experiments disclosing that ALDH contributes to the processes of tumor development and progression through the influence on cells proliferation, cells apoptosis, cells migration as well as cells invasion. For instance, an interesting experiment displays that ALDH (hi)CD44(+)CD24(−) and ALDH (hi)CD44(+)CD133(+) cells present with enhanced tumorigenicity and metastasis compared to ALDH(low)CD44(low/−) cells, indicating that high ALDH severs as an important role in the enhanced malignant and metastatic ability of breast cancer cells [
38]. Another in vitro study reveals that ALDH (high) CD44(+) cells exhibit a higher proliferative, clonogenic and metastatic capacity compared to ALDH(low) CD44(−) cells, suggesting that ALDH has higher tumorigenicity capacity in prostatic cancer [
39]. Therefore, ALDH might act as an oncogene in several carcinomas.
Although some interesting results were found in this meta-analysis, some limitations still existed. At first, there were 14 studies included in this comprehensive meta-analysis, and the numbers of studies were relatively small. Meanwhile, all ovarian cancer patients from this meta-analysis were just from five countries (including China, USA, Germany, Japan as well as Norway). In addition, significant heterogeneity still existed partly due to different characteristics of subjects, different cut off value of ALDH expression or other factors, which might lead to confounding bias. Furthermore, subgroup analyses of studies with other characteristics such as histological type, study region or follow-up duration were not carried out. Further meta-analysis included larger-scale studies is necessary.