Treating Gastric Cancer by Targeting Notch and wnt-Beta-Catenin Cancer Stem-Cell Pathways

Gastric cancer (GC) is the second most common cause of cancer-related death worldwide, and new palliative therapeutic approaches to treat GC are urgent needed. Targeting cancer stem cells (CSC) could be an effective approach to treat GC.2 Recent studies have indicated that Notch signaling and wnt-beta-catenin pathways are crucial for CSC development.1 Plentz and colleagues studied the effects of inactivation of both Notch and wnt-beta-catenin pathways in CSC CD44+ GC cells using a γ-secretase inhibitor (GSI).3 

For their in vitro experiments they used the GC cell line MKN45, since it showed expression of both targets (CD44, Hes1), and measured cell proliferation, wound healing, invasion and tumor sphere assays to analyze the migration, invasive and tumorigenic potential of CD44+ sorted GC-initiating cells after GSI treatment. Western blot analyses of downstream signaling targets of Notch and wnt-beta catenin were tested after GSI treatment. Small interfering RNA (SiRNA) experiments for Notch1 and CD44 were performed in order to confirm the Notch and wnt-beta-catenin pathway crosstalk. The experimental hypothesis of this study was that using GSI to inhibit the CD44-Notch-wnt-beta-catenin axis may provide a possible approach to the treatment of CD44+ GC

For the in vivo analysis, sorted CD44+ cells were subcutaneously injected into NMRI-nu/nu mice which were treated with vehicle or GSI. CD44+ sorted MKN45 cells showed high expression of Hes1 as compared to the CD44- cell population. GSI treatment resulted in effective inhibition of cell proliferation, migration, invasion and tumor sphere formation of the CD44+ cells. Interestingly, among all Notch receptors, Notch1 was found to be important in mediating the crosstalk between Notch and wnt-beta-catenin signaling cascades in CD44+ GC cells. Moreover, silencing of both CD44 and Notch1 by SiRNA showed effective inhibition of downstream targets and reconfirmed the proposed hypothesis of CD44-mediated Notch and wnt/beta-catenin crosstalk in GC cells. The authors concluded that. GSI could be an alternative drug to treat human GC as it effectively targets the CD44+ GC cells and thus, completely reduces the chances of relapse and metastasis of GC. Thus, GSI therapy targeting cancer stem cells may be a viable target for GC treatment and may result in improved clinical outcomes.

  1. Wang R, et al. 2015;Dec 31 [Epub ahead of print]. doi: 10.18632/oncotarget.6805.
  2. Han ME, et al. Anat Cell Biol. 2013;46:8-18.
  3. Plentz RR, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 99.