CD44+ gastric cancer cells with stemness properties are chemoradioresistant and highly invasive

Abstract

CD44 has been confirmed as a cancer stem cell marker in a variety of human cancer cell lines and primary tumours, but whether this marker is applicable to gastric cancer (GC) remains unknown. The responses of CD44+ GC stem-like cells to chemoradiation and the roles they play in cancer invasion are not well understood. In the present study, cell sorting was applied to the poorly differentiated human GC cells to isolate a pure concentration of the CD44+ cell populations (<1% CD44- cells). The stemness properties of the CD44+ cell population were confirmed by two 'gold standard' methods; an in vivo tumourigenicity assay and an in vitro spheroid colony formation assay. In addition, the treatment response was evaluated in CD44+ and CD44- cell fractions that underwent chemoradia-tion. In general, CD44+ stem-like cells tended to respond more poorly to chemoradiation than their non-stem-like counterparts. Further experimentation revealed that the CD44+ stem-like cells that recorded positive scores in the migration and invasion assay in vitro formed invasive tumours in vivo. Therefore, we hypothesized that CD44+ stem &2011;like cells may significantly express invasion-associated genes. Consistent with this prediction, increased expression of the cancer invasion-related genes matrix metalloproteinase (MMP)-1, MMP-2, epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX-2) were detected in the CD44+ stem-like cells. To the best of our knowledge, this is the first study that reveals the correlation between CD44+ GC cells and cancer invasion. By selectively eliminating CD44+ stem-like cells, it may be possible to treat patients with aggressive, non-resectable GCs, as well as preventing the tumours from metastasizing.