Clinical and prognostic significances of cancer stem cell markers in gastric cancer patients: a systematic review and meta-analysis

Abstract

Background: Gastric cancer (GC) is considered one of the most lethal malignancies worldwide, which is accompanied by a poor prognosis. Although reports regarding the importance of cancer stem cell (CSC) markers in gastric cancer progression have rapidly developed over the last few decades, their clinicopathological and prognostic values in gastric cancer still remain inconclusive. Therefore, the current meta-analysis aimed to quantitatively re-evaluate the association of CSC markers expression, overall and individually, with GC patients' clinical and survival outcomes.

Methods: Literature databases including PubMed, Scopus, ISI Web of Science, and Embase were searched to identify the eligible articles. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded or calculated to determine the relationships between CSC markers expression positivity and overall survival (OS), disease-free survival (DFS)/relapse-free survival (RFS), disease-specific survival (DSS)/ cancer-specific survival (CSS), and clinicopathological features.

Results: We initially retrieved 4,425 articles, of which a total of 66 articles with 89 studies were considered as eligible for this meta-analysis, comprising of 11,274 GC patients. Overall data analyses indicated that the overexpression of CSC markers is associated with TNM stage (OR = 2.19, 95% CI 1.84-2.61, P = 0.013), lymph node metastasis (OR = 1.76, 95% CI 1.54-2.02, P < 0.001), worse OS (HR = 1.65, 95% CI 1.54-1.77, P < 0.001), poor CSS/DSS (HR = 1.69, 95% CI 1.33-2.15, P < 0.001), and unfavorable DFS/RFS (HR = 2.35, 95% CI 1.90-2.89, P < 0.001) in GC patients. However, CSC markers expression was found to be slightly linked to tumor differentiation (OR = 1.25, 95% CI 1.01-1.55, P = 0.035). Sub-analysis demonstrated a significant positive relationship between most of the individual markers, specially Gli-1, Oct-4, CD44, CD44V6, and CD133, and clinical outcomes as well as the reduced survival, whereas overexpression of Lgr-5, Nanog, and sonic hedgehog (Shh) was not found to be related to the majority of clinical outcomes in GC patients.

Conclusion: The expression of CSC markers is mostly associated with worse outcomes in patients with GC, both overall and individual. The detection of a combined panel of CSC markers might be appropriate as a prognostic stratification marker to predict tumor aggressiveness and poor prognosis in patients with GC, which probably results in identifying novel potential targets for therapeutic approaches.

Keywords: Cancer stem cells; Clinicopathological characteristics; Gastric cancer; Meta-analysis; Prognostic value.

Fig. 1

Flow chart of the literature search and selection procedure based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines

Fig. 2

Forest plot showing the results of the association between cancer stem cell (CSC) markers expression and overall survival (OS) in gastric cancer (GC)

Fig. 3

Forest plot showing the results of the association between cancer stem cell (CSC) markers expression and disease-free survival/ relapse-free survival (DFS/RFS) in gastric cancer (GC)

Fig. 4

Forest plot showing the results of the association between cancer stem cell (CSC) markers expression and cancer-specific survival/ Disease-specific survival (CSS/ DSS) in gastric cancer (GC)

Fig. 5

Funnel plots for publication bias test with 95%confidence limits. a Cancer stem cell (CSC) markers associated with overall survival (OS); b CSC markers associated with disease-free survival/ relapse-free survival (DFS/RFS); c CSC markers associated with cancer-specific survival/ Disease-specific survival (CSS/DSS)