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Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer

Oncogene volume 38, pages 780–793 (2019)Cite this article

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Abstract

Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial–mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44+ CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44+ CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44− non-CSCs into the undifferentiated CD44+ CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.

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Acknowledgements

We especially thank N Torada, T Ueki, and T Manabe, S Nagai from the Department of Surgery and Oncology, Kyushu University, for providing clinical colorectal cancer tissues. They sincerely thank T. Isobe for development of methods and wonderful lecture. They also thank A. Yurino for providing mice, Yasufumi Uehara for taking confocal microscopy images, T Sugio, T Jiroumaru for performing microarray analysis. Co-workers at our labs, F Hanamura, Yumiko Uehara, K Yamaguchi, K Sagara, K Tsuchihashi, S Arita, supported this work. This study was supported in part by a Grant-in-Aid for Scientific Research (S) (to KA, #16H06391), a Grant-in-Aid for Scientific Research (A) (to KA, #16H02662), a Grant-in-Aid for Scientific Research (C) (to EB, #15K08970), a Grant-in-Aid for Young Scientists (A) (to Y Kikushige #16H06250), a Grant-in-Aid for Young Scientists (B) (to SA, #25860542), a Grant-in-Aid for Scientific Research (B) (to Y Kunisaki, #15H04859), from the JSPS, and a Grant-in-Aid for Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (to TM and Y Kikushige, #25115002) from MEXT, Japan, and the “Project for Cancer Research and Therapeutic Evolution” (to KA, 18cm0106507h0003), and the “Practical Research for Innovative Cancer Control” (to Y Kikushige, 18ck0106196h0003) from Japan Agency for Medical Research and development, AMED, and the Shinnihon Foundation of Advanced Medical Treatment Research (to HA, Y Kikushige, and Y Kunisaki), and a collaborative research grant from AstraZeneca KK (to MN, AZKK Science Promotion Grant).

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Authors and Affiliations

  1. Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

    Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, Yuya Kunisaki, Shinichi Mizuno, Katsuto Takenaka, Shingo Tamura, Yuta Okumura, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Takahiro Maeda, Eishi Baba & Koichi Akashi

  2. Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Eishi Baba

  3. Department of Surgery and Oncology, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

    Masafumi Nakamura

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  1. Michitaka Nakano
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Correspondence to Eishi Baba.

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Ethics statement

Colorectal cancer tissues of 79 patients were obtained upon resection. All human studies were performed in accordance with Declaration of Helsinki principles and the guidelines of the Research Ethics Committee on Human Experimentation of Kyushu University (#28–95) and written informed consent was received from participants prior to inclusion in the study. Supplementary Tables S1 and S2 provide a summary of the clinical information of the colorectal cancer patients analyzed in this study.

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Nakano, M., Kikushige, Y., Miyawaki, K. et al. Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer. Oncogene 38, 780–793 (2019). https://doi.org/10.1038/s41388-018-0480-0

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