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Du, Juan Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Xu, Yanning Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Sasada, Saki Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Oo, Aung Ko Ko Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Hassan, Ghmkin Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University ORCID
Mahmud, Hafizah Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University ORCID
Khayrani, Apriliana Cahya Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Alam, Md Jahangir Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Kumon, Kazuki Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Uesaki, Ryo Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Afify, Said M. Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University ORCID
Mansour, Hager M. Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Nair, Neha Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Zahra, Maram H. Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University
Seno, Akimasa Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University ORCID Kaken ID publons researchmap
Okada, Nobuhiro Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University Kaken ID researchmap
Chen, Ling Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics
Yan, Ting Department of Pathology, Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University
Seno, Masaharu Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University ORCID Kaken ID publons researchmap
Abstract
Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of CSCs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3 beta inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of miPSCs into CSCs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3 beta was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment.
Keywords
2020-06-22
Publication Title
Scientific Reports
Volume
volume10
Issue
issue1
Publisher
NATURE PUBLISHING GROUP
Start Page
9955
ISSN
2045-2322
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© The Author(s) 2020
File Version
publisher
PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1038/s41598-020-66471-2
License
http://creativecommons.org/licenses/by/4.0/
Citation
Du J, Xu Y, Sasada S, et al. Signaling Inhibitors Accelerate the Conversion of mouse iPS Cells into Cancer Stem Cells in the Tumor Microenvironment. Sci Rep. 2020;10(1):9955. Published 2020 Jun 22. doi:10.1038/s41598-020-66471-2
Funder Name
Japan Society for the Promotion of Science
助成番号
25242045
26640079
18K15243