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.

Stem Cells and Cancer Stem Cells: The Jekyll and Hyde Scenario and Their Implications in Stem Cell Therapy

“…In lung cancer, CD38 expression promotes cell growth by fortifying the cells' anchorage ability, invasion, and xenograft growth in nude mice [31]. However, the development of malignancy in lung cancer was reduced with the deletion of ADP-ribose-acceptor hydrolase (ARH)-1 from the CD38 gene [31]. These findings support that CD38 plays a critical role in cancer prognosis and development.…”

“…The immunosuppressive role of CD38 served as the escape mechanism for tumour cells from PD-1/PD-l1 blockade whereby it inhibited CD8+ T-cell activity through the adenosine receptor signalling pathway [30]. Expression of CD38 was found in 15-23% of cancer incidents with a strong correlation to the inflammatory mechanism in the tumour microenvironment [31]. Normally, the malignancies are haematological, such as multiple myeloma, NK/T cell lymphoma, and T-cell acute lymphoblastic leukemia [31].…”

“…Expression of CD38 was found in 15-23% of cancer incidents with a strong correlation to the inflammatory mechanism in the tumour microenvironment [31]. Normally, the malignancies are haematological, such as multiple myeloma, NK/T cell lymphoma, and T-cell acute lymphoblastic leukemia [31]. In lung cancer, CD38 expression promotes cell growth by fortifying the cells' anchorage ability, invasion, and xenograft growth in nude mice [31].…”

“…Normally, the malignancies are haematological, such as multiple myeloma, NK/T cell lymphoma, and T-cell acute lymphoblastic leukemia [31]. In lung cancer, CD38 expression promotes cell growth by fortifying the cells' anchorage ability, invasion, and xenograft growth in nude mice [31]. However, the development of malignancy in lung cancer was reduced with the deletion of ADP-ribose-acceptor hydrolase (ARH)-1 from the CD38 gene [31].…”

Stem Cell Biomarkers and Tumorigenesis in Gastric Cancer

“…However, there are some conflicting opinions on this relationship in GCs, because of the diversity in the methodology, sample sizes, and research participants. Thus, there is a need to better establish the relationship using meta-analysis and clinical data to generate new biomarkers [ 10 ].…”