Abstract
BackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.
Highlights
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)
CD133 signature genes in GCs To evaluate the gene expression associated with the CD133 stem cell marker in GCs, we performed gene expression profiling of three gastric cancer cell lines (KATO-III, SNU216, and SNU601)
The CD133-up expression signatures of GC and glioblastoma multiforme (GBM) were correlated with each other as well as with two embryonic stem cells (ESC) expression signatures. This suggested that the CD133 expression signature levels were consistent across tumor types (GBM in vivo and GC in Clinicopathological features associated with CD133 expression signature in GC We further evaluated the CD133 expression signature in terms of their correlation with or enrichment of the clinicopathological features of GC as available in the the Cancer Genome Atlas (TCGA) consortium (Fig. 3)
Summary
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). Immunohistochemistry (IHC)-based quantification of expressed CD133 protein levels has been proposed as a GC prognostic marker and CD133 positivity indicates poor prognosis as well as chemoresistance and disease progression of GC [5,6,7,8,9,10,11,12]. Those reports have not considered the known heterogeneity issues of GCs [13]. It is important to understand the molecular mechanisms and underlying biology of CD133associated cancer stem cells in a milieu of heterogeneous, non-tumor cells such as tumor-infiltrating stromal cells for a proper evaluation of this prognostic marker
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