Identification of a subpopulation of long-term tumor-initiating cells in colon cancer

Abstract

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.

VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling

“…CD44 is a multi-structural multifunctional transmembrane glycoprotein capable of binding extracellular matrix components to promote cell adhesion as well as cell surface growth factor binding, maintaining interactions between cells and matrix[ 37 ]. CD44-positive CSCs perceive environmental changes that modulate signal transduction, regulating the stemness characteristics of CSCs[ 38 ]. Somatic cells can transform into pluripotent stem cells through the transient ectopic overexpression of transcription factors such as Oct4, SOX2, and Nanog, which participate in the regulation CSC self-renewal and development[ 39 ].…”

Efficacy and safety of natural killer cells injection combined with XELOX chemotherapy in postoperative patients with stage III colorectal cancer in China: a prospective randomised controlled clinical trial study protocol

“…17 18 Recent evidence suggests that cancer stem cells (CSCs), which are a subpopulation of cells with stem cell-like characteristics, play a crucial role in various aspects of CRC including initiation, progression, relapse, metastasis. [19][20][21][22] They are resistant to radiation and chemotherapy drugs. 22 23 It has been observed that conventional treatments like surgery and chemotherapy primarily target the bulk of the tumour, but they often fail to eliminate CSCs.…”

“…Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hindered by several factors, including inadequate tumour infiltration, persistence/activation in the TME 17 18. Recent evidence suggests that cancer stem cells (CSCs), which are a subpopulation of cells with stem cell-like characteristics, play a crucial role in various aspects of CRC including initiation, progression, relapse, metastasis 19–22. They are resistant to radiation and chemotherapy drugs 22 23.…”

Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation

“…Less DNA damage in CSCs as compared to their non-CSC counterparts was reported in several studies that quantified DNA damage after genotoxic therapies or at baseline levels. This quantification was made, e.g., using residual γH2A.X foci analysis (for example, more efficient foci resolution was shown for lung cancer CD133 + cells [ 12 ], murine cancer CD29 + CD24 high cells [ 13 ], head and neck squamous cell carcinoma (HNSCC) ALDH + cells [ 14 ], glioblastoma CSC populations in patient-derived cell lines [ 15 ]) or by comet assay (for example the lower amount of DNA damage was found in glioblastoma patient-derived CD133 + cells [ 16 ], CD133 + CD44 + colon cancer cells [ 17 ] and murine cancer CD29 + CD24 high cells [ 13 ]). However, some studies showed no difference in the levels of DNA damage quantified in the same way in CSCs and non-CSC populations [ 18 , 19 , 20 ].…”