A meta-analysis and The Cancer Genome Atlas data of prostate cancer risk and prognosis using epithelial cell adhesion molecule (EpCAM) expression

Prostate cancer (PCa) is the second commonest malignancy and the fifth leading cause of cancer-related deaths in men [1]. Based on GLOBOCAN estimates, approximately 1.3 million new cases were clinically diagnosed with PCa in 2018, leading to approximately 359,000 PCa-related deaths worldwide [1]. Several therapeutic strategies, including radical prostatectomy and radiotherapy, have shown a better clinical outcome for patients with early-stage PCa [2, 3]. In contrast, patients with advanced stage PCa have distant metastases and consequently, worse prognosis because of the lack of the effective treatment options [4, 5]. Therefore, a novel molecular biomarker is required to improve the prognosis of patients with PCa.

Cancer stem cells (CSCs) are a small group of cells within tumors and are responsible for self-renewal, uncontrolled differentiation, and tumorigenicity [6, 7]. CSCs contribute to cancer development, progression, and metastasis [8‐10]. Epithelial cell adhesion molecule (EpCAM), known as epithelial-specific antigen (ESA) or CD326, a membrane glycoprotein, plays an important role in Ca2+ independent hemophilic cell-to-cell adhesion, cell signaling, migration, proliferation, and differentiation [11, 12]. The presence of CSCs in PCa may partially play a role in cancer progression, metastasis, and chemoresistance [13, 14]. EpCAM is identified as a CSC marker and a potential therapeutic target for cancer [15]. EpCAM is expressed in many types of human cancer, such as breast cancer, gastric cancer, and colorectal cancer [16‐18]. Recent studies also demonstrated that high EpCAM expression may predict poor clinical outcome in breast cancer [19], ovarian carcinoma [20], and hepatocellular carcinoma [21]. Some studies reported that EpCAM was frequently expressed and associated with worse prognosis of patients with PCa [22, 23].

The development of PCa develops involves the transition of normal epithelium to benign prostatic epithelium, and subsequent progression to malignant carcinoma through multiple sequences [24‐26]. The role of EpCAM expression in PCa development and progression remains controversial. Ni 2013 et al. reported that the frequency of EpCAM expression was similar in PCa and benign prostatic tissue samples [22]. In contrast, Li et al. showed that EpCAM expression was notably higher in PCa than benign prostatic tissue samples [27]. Thus, the primary objective of this study was to identify the role of EpCAM in determining the risk of PCa development. The secondary objective was to perform a meta-analysis to assess the clinicopathological and prognostic value of EpCAM in PCa.

CSCs, a special subpopulation of tumor cells, have the ability to form the bulk of the tumor and contribute to tumor progression and relapse [9]. Therefore, eradication of CSCs is considered as a crucial challenge for a successful cancer therapy [37]. EpCAM is identified as a CSC marker that is closely linked to tumor progression [38]. EpCAM plays an important role in the cell-cell adhesion, cell signaling, migration, proliferation, and differentiation [39]. EpCAM also plays an important role in mediating migration of immune cells [38]. EpCAM in PCa is associated with tumor progression and metastasis and therapeutic resistance via the PI3K/Akt/mTOR signaling pathway [22]. EpCAM is frequently overexpressed across a wide range of human cancer, including pancreatic adenocarcinoma, breast cancer, ovarian cancer, and head and neck squamous cell cancer [40]. EpCAM overexpression is correlated with worse prognosis in some types of cancer [19, 41, 42]. Some studies reported that EpCAM is highly expressed in patients with PCa [22, 27, 33, 34]. However, the function of EpCAM and its clinical effect in PCa remains largely unclear. In this study, we analyzed the clinicopathological significance of EpCAM expression and its role in the prognosis of PCa.

The pooled data demonstrated that EpCAM expression was significantly higher in PCa than in benign and normal prostatic tissue samples, suggesting that EpCAM overexpression may be associated with the development of PCa. Our results were consistent with the previous studies that EpCAM was expressed more frequently in PCa than in benign [23, 27] and normal prostatic tissue samples [22, 35]. Moreover, TCGA data also showed that EpCAM expression was notably increased in PCa than in normal tissue samples.

We further analyzed whether EpCAM overexpression was correlated with the clinicopathological characteristics of patients with PCa. EpCAM overexpression was not linked to pT stage and lymph node metastasis, but was associated with Gleason score and bone metastasis. TCGA data revealed that EpCAM overexpression was not closely correlated with the clinicopathological characteristics in 495 patients with PCa, including age, pT stage, lymph node metastasis, number of lymph node, prostate-specific antigen (PSA) level, Gleason score, and biochemical recurrence. The pooled analyses suggested that EpCAM overexpression may predict bone metastasis. However, as the sample size was small, the relationship between EpCAM overexpression and bone metastasis requires further investigation.

EpCAM overexpression was reported to be closely associated with 5-year worse biochemical recurrence free-survival using multivariate Cox proportional-hazards regression analysis in 102 patients with PCa [23]; this suggests that EpCAM overexpression may be a potential prognostic biomarker for predicting poor biochemical recurrence free-survival. However, no association was found between EpCAM overexpression and overall survival of patients with PCa.

Our result showed no correlation between EpCAM overexpression and lymph node metastasis among two studies with 430 patients with PCa, which was consistent with the study of Went 2006 et al. [36] among a large cohort (388 patients). Heterogeneity was found in the correlation of PCa and benign prostatic tissue samples (P = 0.043). When we removed the study by Ni 2013 et al. [22], the re-calculated OR remained significant with no obvious evidence of heterogeneity. The analysis suggested that our results were reliable. The reasons of the heterogeneity were not very clear; the inappropriate conditions of IHC methods may cause the bias.

There were some limitations in the current study. First, as none of the present meta-analyses included ≥10 studies, we could not examine and rule out the risk of the potential publication bias. Although we systematically searched PubMed, EMBASE, Cochrane Library, EBSCO, Wanfang, and CNKI databases to minimize the potential bias, the eligible studies were restricted to papers published in English or Chinese. Moreover, studies published in language other than English and Chinese, unpublished papers, or conference abstracts were excluded based on incomplete information. Furthermore, studies with negative results are less likely to be published than papers with positive results. These reasons may cause potential bias. Second, the main ethnic population in this meta-analysis was European; other ethnic groups, such as Asians and Africans, were under-represented. Third, the studies regarding the associations of EpCAM overexpression with bone metastasis and biochemical recurrence free-survival were relatively small. Further studies with large sample size are needed to further confirm these results. Finally, the cut-off values of EpCAM expression were different among some studies, which showed inconsistent definitions for “negative” and “positive,” leading to the potential heterogeneity. Therefore, the results need to be interpreted with caution. EpCAM expression should be defined as positive or negative based on a uniform standard in the future.

In conclusion, the current meta-analysis suggested that EpCAM expression was significantly high in PCa than in benign and normal prostatic tissue samples. EpCAM overexpression was not associated with age, pT stage, lymph node metastasis, number of lymph node, prostate-specific antigen (PSA) level, biochemical recurrence, and overall survival. EpCAM overexpression may be related to the development of bone metastasis and worse biochemical recurrence free-survival of PCa. Our results should be interpreted with caution owing to the small sample size. Additional large-scale prospective studies are required to further validate our findings.