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Int J Biol Sci 2021; 17(7):1644-1659. doi:10.7150/ijbs.58612 This issue Cite

Research Paper

Wnt/β-catenin Signaling Inhibitors suppress the Tumor-initiating properties of a CD44⁺CD133⁺ subpopulation of Caco-2 cells

Junghoon Kim, Kyeng-Won Choi, Jungwoon Lee, Jaeyoung Lee, Seonock Lee, Ruijing Sun, Jungho Kim^✉

Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul 04107, Korea.

✉ Corresponding author: Jungho Kim, Lab. of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul 04107, Korea. Tel: 82-2-705-8461; Fax: 82-2-705-8412; E-mail: jkimac.kr.

Abstract

Tumor-initiating cells or cancer stem cells are a subset of cancer cells that have tumorigenic potential in human cancer. Although several markers have been proposed to distinguish tumor-initiating cells from colorectal cancer cells, little is known about how this subpopulation contributes to tumorigenesis. Here, we characterized a tumor-initiating cell subpopulation from Caco-2 colorectal cancer cells. Based on the findings that Caco-2 cell subpopulations express different cell surface markers, we were able to discriminate three main fractions, CD44^-CD133^-, CD44^-CD133⁺, and CD44⁺CD133⁺ subsets, and characterized their biochemical and tumorigenic properties. Our results show that CD44⁺CD133⁺ cells possessed an unusual capacity to proliferate and could form tumors when transplanted into NSG mice. Additionally, primary tumors grown from CD44⁺CD133⁺ Caco-2 cells contained mixed populations of CD44⁺CD133⁺ and non-CD44⁺CD133⁺ Caco-2 cells, indicating that the full phenotypic heterogeneity of the parental Caco-2 cells was re-created. Notably, only the CD44⁺CD133⁺ subset of Caco-2-derived primary tumors had tumorigenic potential in NSG mice, and the tumor growth of CD44⁺CD133⁺ cells was faster in secondary xenografts than in primary transplants. Gene expression analysis revealed that the Wnt/β-catenin pathway was over-activated in CD44⁺CD133⁺ cells, and the growth and tumorigenic potential of this subpopulation were significantly suppressed by small-molecule Wnt/β-catenin signaling inhibitors. Our findings suggest that the CD44⁺CD133⁺ subpopulation from Caco-2 cells was highly enriched in tumorigenic cells and will be useful for investigating the mechanisms leading to human colorectal cancer development.

Keywords: Caco-2, Tumor-initiating cells, CD44, CD133, Tumorigenic potential, Wnt/β-catenin signaling inhibitor, XAV939, IWR-1

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