Impact of in vitro driven expression signatures of CD133 stem cell marker and tumor stroma on clinical outcomes in gastric cancers

The CD133 transmembrane protein is a well-recognized stem cell marker that has been used to isolate putative cancer stem cell populations from gastric cancers (GCs). However, the molecular features or biomarkers underlying CD133 are largely unknown in GCs.

We performed gene expression profiling of CD133+ and CD133- cells sorted by flow cytometry from three GC cell lines to identify the CD133 expression signatures of GC. The CD133 expression signatures were investigated across publicly available expression profiles of multiple tumor types including GC and also for their relationship with patient survival.

The CD133 signature genes defined as 177 upregulated genes and 129 downregulated genes in CD133+ cells compared to CD133- cells were enriched with genes involving the cell cycle and cytoskeleton, implying that cancer stem cells with unlimited self-renewal play cancer-initiating roles. The CD133 expression signatures in GC expression profiles were positively correlated with those of brain tumors expressing CD133 and human embryonic stem cells, emphasizing the transcriptional similarities across stem cell-related expression signatures. We also found that these stem cell expression signatures were inversely correlated with those representing tumor infiltrating immune and stromal cells. Additionally, high CD133 expression signatures were found in intestinal subtypes and low tumor stage GCs as well as in those with microsatellite instabilities and high mutation burdens. As examined across 20 additional tumor types, both the expression signatures representing CD133 and stromal cells were unfavorable prognostic features; however, their impact were variable across tumor types.

The transcriptional activities of CD133 and those of stromal cells representing the activity of stem cells and level of epithelial-to-mesenchymal transition, respectively, may be inversely correlated with each other across multiple tumor types including GC. This relationship may be a confounding factor and should therefore be considered when evaluating the clinical relevance of stem cell-related markers.