Long-term tumor-initiating cells (LT-TICs) are viewed as a quantifiable target for colon cancer therapy owing to their extensive self-renewal and tumorigenic and metastatic capacities. However, it is unknown which subpopulation of colon cancer cells contains LT-TICs. Here, based on the methods for isolating and identifying cancer stem cells (CSCs) and the functional features of LT-TICs, we aimed to identify a subpopulation of LT-TICs. Among the six cell lines assessed, our results showed that CD133 and CD44 coexpression was only detected in HCT116 and HT29 cell lines. In HCT116 and HT29 cells, CD133+CD44+ cells not only shared the extensive tumorigenic potential of LT-TICs but also functionally reproduced the behaviors of LT-TICs that drive tumor metastasis formation, suggesting that CD133+CD44+ cells are a typical representation of LT-TICs in colon cancer. Mechanistically, the enhanced capacity of CD133+CD44+ cells to drive metastasis involves the upregulated expression of Wnt-, EMT-, and metastasis-related genes in these cells. Additionally, CD133+CD44+ cells presented significant chemoresistance compared with corresponding nontumorigenic CD133-CD44- cells following exposure to oxaliplatin or 5-FU. Accordingly, CD133+CD44+ cells contained lower ROS levels than CD133-CD44- cells, and the low ROS levels in CD133+CD44+ cells were related to the enhancement of antioxidant defense systems. More importantly, CD133+CD44+ cells developed less DNA damage after exposure to chemotherapeutics than CD133-CD44- cells. In conclusion, we identified a subpopulation of LT-TICs in colon cancer.

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