Targeting Gastric Cancer Stem Cells through Developmental Pathways: Hypothesis

Cancer stem cells (CSCs) have been defined as a unique subpopulation in tumors, endowed with the capacity to initiate tumor progression, and maintain self‐renewal as well as metastatic potential. Recently, more evidences strongly indicate the existence of CSCs in solid tumors of wide variety of organs such as breast, brain and stomach. Recent studies suggest that a special subpopulation of gastric cancer cells with specific marker namely CD44, shows spheroid colony formation in serum free media in vitro, as well as tumorigenic capacity in immunodeficient animal model in vivo. In addition, current evidences indicate that one of the major reasons for failure of chemotherapy and radiotherapy is the existence of CSCs with resistant mechanisms against current therapeutic strategies. Growing evidence recommended that pathways which are responsible for regulation of normal stem cell self‐renewal and differentiation may also represent regulatory roles in maintenance of cancer cells and CSCs. Two major therapeutic approaches for elimination of CSCs are differentiation therapy and inhibition of important pathways involved in maintenance of CSCs such as notch signaling.It is hypothesized that with inhibition of notch signaling by means of DAPT(gamma‐secretase‐inhibitor), silencing Ral pathway as well as inducing differentiation by means of all‐trance retinoic acid (ATRA) in CD44+ gastric cancer stem cells, we can target this small population and eventually eliminate them by sensitizing these cells to chemotherapy and radiotherapy as well as induction of apoptosis in them.