Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma

Three-dimensional cell culture methods are viable in vitro approaches that facilitate the examination of biological features cancer cells present in vivo. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells in porous alginate scaffolds can generate organoid-like spheroids that mi...

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Main Authors:	Takai, Atsushi, Fako, Valerie, Dang, Hien, Forgues, Marshonna, Yu, Zhipeng, Budhu, Anuradha, Wang, Xin Wei
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754778/

id	pubmed-4754778
recordtype	oai_dc
spelling	pubmed-47547782016-02-24 Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma Takai, Atsushi Fako, Valerie Dang, Hien Forgues, Marshonna Yu, Zhipeng Budhu, Anuradha Wang, Xin Wei Article Three-dimensional cell culture methods are viable in vitro approaches that facilitate the examination of biological features cancer cells present in vivo. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells in porous alginate scaffolds can generate organoid-like spheroids that mimic numerous features of glandular epithelium in vivo, such as acinar morphogenesis and apical expression patterns of EpCAM, a hepatic stem/progenitor cell marker highly expressed in a subset of HCC with stemness features. We show that the activation of Wnt/β-catenin signaling, an essential pathway for maintaining HCC stemness, is required for EpCAM+ HCC spheroid formation as well as the maintenance of the acinous structure. Furthermore, we demonstrate that EpCAM+ HCC cells cultured as spheroids are more sensitive to TGF/β-induced epithelial-mesenchymal transition with highly tumorigenic and metastatic potential in vivo compared to conventional two-dimensional (2D) culture. In addition, HCC cells in EpCAM+ spheroids are more resistant to chemotherapeutic agents than 2D-cultured cells. The alginate scaffold-based organotypic culture system is a promising, reliable, and easy system that can be configured into a high throughput fashion for the identification of critical signaling pathways and screening of molecular drug targets specific for HCC. Nature Publishing Group 2016-02-16 /pmc/articles/PMC4754778/ /pubmed/26880118 http://dx.doi.org/10.1038/srep21174 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Takai, Atsushi Fako, Valerie Dang, Hien Forgues, Marshonna Yu, Zhipeng Budhu, Anuradha Wang, Xin Wei
spellingShingle	Takai, Atsushi Fako, Valerie Dang, Hien Forgues, Marshonna Yu, Zhipeng Budhu, Anuradha Wang, Xin Wei Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma
author_facet	Takai, Atsushi Fako, Valerie Dang, Hien Forgues, Marshonna Yu, Zhipeng Budhu, Anuradha Wang, Xin Wei
author_sort	Takai, Atsushi
title	Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma
title_short	Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma
title_full	Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma
title_fullStr	Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma
title_full_unstemmed	Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma
title_sort	three-dimensional organotypic culture models of human hepatocellular carcinoma
description	Three-dimensional cell culture methods are viable in vitro approaches that facilitate the examination of biological features cancer cells present in vivo. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells in porous alginate scaffolds can generate organoid-like spheroids that mimic numerous features of glandular epithelium in vivo, such as acinar morphogenesis and apical expression patterns of EpCAM, a hepatic stem/progenitor cell marker highly expressed in a subset of HCC with stemness features. We show that the activation of Wnt/β-catenin signaling, an essential pathway for maintaining HCC stemness, is required for EpCAM+ HCC spheroid formation as well as the maintenance of the acinous structure. Furthermore, we demonstrate that EpCAM+ HCC cells cultured as spheroids are more sensitive to TGF/β-induced epithelial-mesenchymal transition with highly tumorigenic and metastatic potential in vivo compared to conventional two-dimensional (2D) culture. In addition, HCC cells in EpCAM+ spheroids are more resistant to chemotherapeutic agents than 2D-cultured cells. The alginate scaffold-based organotypic culture system is a promising, reliable, and easy system that can be configured into a high throughput fashion for the identification of critical signaling pathways and screening of molecular drug targets specific for HCC.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754778/
_version_	1613539035682177024

Three-dimensional Organotypic Culture Models of Human Hepatocellular Carcinoma

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