Abstract
The prognosis of patients with gastric cancer (GC) is still unsatisfying. Numerous markers of gastric cancer stem cells (GCSCs) have been identified and were thought to be related to cancer aggressiveness. However, the roles of GCSC markers in GC patients’ prognosis and immune infiltration remain unknown. Expression of GCSC markers was analyzed using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). Their associations with clinicopathological parameters were analyzed using UALCAN and LinkedOmics. Alternations and protein expression of GCSC markers were analyzed by cBioPortal and the Human Protein Atlas databases, respectively. The prognostic significance of GCSC markers was evaluated using Kaplan-Meier plotter. Correlations between the expression of GCSC markers and immune infiltration along with biomarkers of tumor-infiltrating immune cells (TIICs) were assessed combined Tumor Immune Estimation Resource and GEPIA. GeneMANIA was used to discover the interactive genes of GCSC markers, and enrichment analysis was performed using Database for Annotation, Visualization, and Integrated Discovery server. We identified six GCSC markers significantly up-expressed in GC, compared with normal stomach tissues. Among them, the overexpression of ICAM1, THY1, and CXCR4 significantly indicated adverse, while EPCAM indicated beneficial clinicopathological features of GC patients. The up-regulation of CXCR4 showed unfavorable prognostic significance, whereas EPCAM and TFRC showed the opposite. The six GCSC markers were all correlated with the infiltration and activation of distinct TIICs. Especially, ICAM1, THY1, and CXCR4 showed strongly positive correlations with tumor-associated macrophages. Besides, chemokine, Toll-like receptor, NF-kappa B, and HIF-1 signaling pathways might be involved in the regulation of GCSC markers on cancer development. This study proposed that GCSC markers might be promising targets of GC treatment to weaken cancer stem-like properties and strengthen anticancer immunity.
Highlights
Gastric cancer (GC) is the fifth most frequently diagnosed and the third leading cause of cancer mortality in the world (Bray et al, 2018)
It turned out that eight gastric Cancer stem cells (CSCs) (GCSCs) markers were significantly higher expressed in gastric cancer (GC) than normal stomach tissues in Oncomine (Figure 1A) and Gene Expression Profiling Interactive Analysis (GEPIA) (Figure 1B), respectively
Even though there were some differences in the results from the two databases, the expressions of epithelial cell adhesion molecules (EPCAM), ICAM1, THY1, TFRC, LGR5, and CXCR4 were consistently significantly elevated in both databases, so the six GCSC markers were included in our following study (Figure 1C)
Summary
Gastric cancer (GC) is the fifth most frequently diagnosed and the third leading cause of cancer mortality in the world (Bray et al, 2018). Chemotherapy and targeted therapy can improve survival and quality of life of unresectable or metastatic GC patients, while drug resistance frequently leads to poor outcomes (Jones and Smyth, 2020; Wei et al, 2020). Abundant studies demonstrated that CSCs share markers with tissue stem cells, and biomarkers of gastric CSCs (GCSCs) have been explored in recent decades (Nguyen et al, 2017). The CSC theory provides a meaningful pointcut that targeting the vital markers or pathways involved in the maintenance of CSCs might influence their stem cell-like properties to eliminate cancer
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