IFN-γ selectively exerts pro-apoptotic effects on tumor-initiating label-retaining colon cancer cells

• Prove the stem cell-like traits of label retaining cells in colon cancer cells.
• The stem cell-like traits decreased with label dilution.
• LRCCs and Lgr5+ cells are two different populations.
• Label retaining cells especially sensitive to the apoptotic effect of IFN-γ.

Label-retaining cancer cells (LRCCs) represent a novel population of stem-like cancer cells exhibiting slow cycling, chemoresistance and tumor-initiating capacities; however, their properties remain unclear, and approaches to eradicate LRCCs remain elusive. Here, we report that colon cancer cells with high fluorescent intensity, referred to as LRCCs, have the greatest cancer stem cell (CSC)-like capacities and that they preferentially express CSC markers and stemness-related genes. Moreover, we found that Lgr5, which has been reported to be a marker of rapid cycling CSCs, is almost negatively expressed in LRCCs but that its expression is gradually increased in the differentiation process of LRCCs. Interestingly, we found that LRCCs are especially sensitive to the pro-apoptotic effect of IFN-γ treatment both in vitro and in vivo because LRCCs possess higher IFN-γR levels compared with non-LRCCs, which results in the upregulation of the apoptosis pathway after IFN-γ treatment. Furthermore, we found that IFN-γ shows synergistic effects with the conventional anticancer drug Oxaliplatin to eliminate both LRCCs and non-LRCCs. In conclusion, this is the first study to suggest that LRCCs, as a distinct tumor-initiating population, can be selectively eradicated by IFN-γ, which may provide a novel therapeutic strategy for colon cancer treatment.