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Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells

Colon cancer stem cells (CSCs) have been shown to be responsible for the recurrence and metastasis of colorectal cancer (CRC). As a crucial microenvironmental factor, extracellular matrix (ECM) stiffness is known to affect the stemness of CSCs. Recently, fibrin deposition in the stroma of CRC was de...

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Autores principales: Zhang, Meng, Xu, Cong, Wang, Hai-zhou, Peng, Ya-nan, Li, Hai-ou, Zhou, Yun-jiao, Liu, Shi, Wang, Fan, Liu, Lan, Chang, Ying, Zhao, Qiu, Liu, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377646/
https://www.ncbi.nlm.nih.gov/pubmed/30770783
http://dx.doi.org/10.1038/s41419-019-1309-7
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author Zhang, Meng
Xu, Cong
Wang, Hai-zhou
Peng, Ya-nan
Li, Hai-ou
Zhou, Yun-jiao
Liu, Shi
Wang, Fan
Liu, Lan
Chang, Ying
Zhao, Qiu
Liu, Jing
author_facet Zhang, Meng
Xu, Cong
Wang, Hai-zhou
Peng, Ya-nan
Li, Hai-ou
Zhou, Yun-jiao
Liu, Shi
Wang, Fan
Liu, Lan
Chang, Ying
Zhao, Qiu
Liu, Jing
author_sort Zhang, Meng
collection PubMed
description Colon cancer stem cells (CSCs) have been shown to be responsible for the recurrence and metastasis of colorectal cancer (CRC). As a crucial microenvironmental factor, extracellular matrix (ECM) stiffness is known to affect the stemness of CSCs. Recently, fibrin deposition in the stroma of CRC was demonstrated to be responsible for tumor development. In this study, we used salmon fibrin gel to provide a 3D ECM for colon cancer cells and investigated its effects on cell growth as well as the underlying mechanisms. Compared with stiff 420 Pascal (Pa) and 1 050 Pa gels, 90 Pa soft fibrin gel was most efficient at isolating and enriching tumor colonies. The size and number of colony formation negatively correlated with gel stiffness. Specifically, these tumor colonies exhibited efficient tumorigenicity, upregulated stem cell markers, and had anti-chemotherapeutic properties and were thus named tumor-repopulating cells (TRCs). More importantly, the self-renewal molecule Nanog was sharply induced in 3D-cultured colon TRCs; further, Nanog siRNA significantly inhibited colony formation, suggesting the indispensable role of Nanog in TRC growth. A subsequent mechanistic study illustrated that Nanog expression could be modulated through fibrin gel stiffness-induced DAB2IP/PI3K/FOXA1 signaling in colon TRCs.
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spelling pubmed-63776462019-02-19 Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells Zhang, Meng Xu, Cong Wang, Hai-zhou Peng, Ya-nan Li, Hai-ou Zhou, Yun-jiao Liu, Shi Wang, Fan Liu, Lan Chang, Ying Zhao, Qiu Liu, Jing Cell Death Dis Article Colon cancer stem cells (CSCs) have been shown to be responsible for the recurrence and metastasis of colorectal cancer (CRC). As a crucial microenvironmental factor, extracellular matrix (ECM) stiffness is known to affect the stemness of CSCs. Recently, fibrin deposition in the stroma of CRC was demonstrated to be responsible for tumor development. In this study, we used salmon fibrin gel to provide a 3D ECM for colon cancer cells and investigated its effects on cell growth as well as the underlying mechanisms. Compared with stiff 420 Pascal (Pa) and 1 050 Pa gels, 90 Pa soft fibrin gel was most efficient at isolating and enriching tumor colonies. The size and number of colony formation negatively correlated with gel stiffness. Specifically, these tumor colonies exhibited efficient tumorigenicity, upregulated stem cell markers, and had anti-chemotherapeutic properties and were thus named tumor-repopulating cells (TRCs). More importantly, the self-renewal molecule Nanog was sharply induced in 3D-cultured colon TRCs; further, Nanog siRNA significantly inhibited colony formation, suggesting the indispensable role of Nanog in TRC growth. A subsequent mechanistic study illustrated that Nanog expression could be modulated through fibrin gel stiffness-induced DAB2IP/PI3K/FOXA1 signaling in colon TRCs. Nature Publishing Group UK 2019-02-15 /pmc/articles/PMC6377646/ /pubmed/30770783 http://dx.doi.org/10.1038/s41419-019-1309-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zhang, Meng
Xu, Cong
Wang, Hai-zhou
Peng, Ya-nan
Li, Hai-ou
Zhou, Yun-jiao
Liu, Shi
Wang, Fan
Liu, Lan
Chang, Ying
Zhao, Qiu
Liu, Jing
Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells
title Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells
title_full Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells
title_fullStr Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells
title_full_unstemmed Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells
title_short Soft fibrin matrix downregulates DAB2IP to promote Nanog-dependent growth of colon tumor-repopulating cells
title_sort soft fibrin matrix downregulates dab2ip to promote nanog-dependent growth of colon tumor-repopulating cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377646/
https://www.ncbi.nlm.nih.gov/pubmed/30770783
http://dx.doi.org/10.1038/s41419-019-1309-7
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