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The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis

Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin...

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Autores principales: Peng, Zheng, Hao, Meng, Tong, Haibo, Yang, Hongmei, Huang, Bin, Zhang, Zhigang, Luo, Kathy Qian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379399/
https://www.ncbi.nlm.nih.gov/pubmed/35982891
http://dx.doi.org/10.7150/ijbs.72367
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author Peng, Zheng
Hao, Meng
Tong, Haibo
Yang, Hongmei
Huang, Bin
Zhang, Zhigang
Luo, Kathy Qian
author_facet Peng, Zheng
Hao, Meng
Tong, Haibo
Yang, Hongmei
Huang, Bin
Zhang, Zhigang
Luo, Kathy Qian
author_sort Peng, Zheng
collection PubMed
description Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin-α(5)β(1) from liver cancer cells as the primary responsible molecules utilizing CRISPR/Cas9 gene-editing technology. Coculture led to the formation of 3D multilayer microstructures, and obvious fibronectin remodeling was caused by upregulated integrin-α(5)β(1), which greatly promoted cell growth in 3D microstructures. Integrin-α(5) was more sensitive and specific than integrin-β(1) in this process. Subsequent mechanistic exploration revealed the activation of integrin-Src-FAK, AKT and ERK signaling pathways. Importantly, the growth-promoting effect of HIIs was verified in a xenograft tumor model, in which more blood vessels were observed in bigger tumors derived from the coculture group than that derived from monocultured groups. Hence, we conducted triculture by introducing human umbilical vein endothelial cells, which aligned to and differentiated along multilayer microstructures in an integrin-α(5)β(1) dependent manner. Furthermore, fibronectin, integrin-α(5), and integrin-β(1) were upregulated in 52 HCC tumors, and fibronectin was related to microvascular invasion. Our findings identify fibronectin, integrin-α(5), and integrin-β(1) as tumor microenvironment-related targets and provide a basis for combination targeted therapeutic strategies for future HCC treatment.
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spelling pubmed-93793992022-08-17 The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis Peng, Zheng Hao, Meng Tong, Haibo Yang, Hongmei Huang, Bin Zhang, Zhigang Luo, Kathy Qian Int J Biol Sci Research Paper Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin-α(5)β(1) from liver cancer cells as the primary responsible molecules utilizing CRISPR/Cas9 gene-editing technology. Coculture led to the formation of 3D multilayer microstructures, and obvious fibronectin remodeling was caused by upregulated integrin-α(5)β(1), which greatly promoted cell growth in 3D microstructures. Integrin-α(5) was more sensitive and specific than integrin-β(1) in this process. Subsequent mechanistic exploration revealed the activation of integrin-Src-FAK, AKT and ERK signaling pathways. Importantly, the growth-promoting effect of HIIs was verified in a xenograft tumor model, in which more blood vessels were observed in bigger tumors derived from the coculture group than that derived from monocultured groups. Hence, we conducted triculture by introducing human umbilical vein endothelial cells, which aligned to and differentiated along multilayer microstructures in an integrin-α(5)β(1) dependent manner. Furthermore, fibronectin, integrin-α(5), and integrin-β(1) were upregulated in 52 HCC tumors, and fibronectin was related to microvascular invasion. Our findings identify fibronectin, integrin-α(5), and integrin-β(1) as tumor microenvironment-related targets and provide a basis for combination targeted therapeutic strategies for future HCC treatment. Ivyspring International Publisher 2022-08-01 /pmc/articles/PMC9379399/ /pubmed/35982891 http://dx.doi.org/10.7150/ijbs.72367 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Peng, Zheng
Hao, Meng
Tong, Haibo
Yang, Hongmei
Huang, Bin
Zhang, Zhigang
Luo, Kathy Qian
The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
title The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
title_full The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
title_fullStr The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
title_full_unstemmed The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
title_short The interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
title_sort interactions between integrin α(5)β(1) of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9379399/
https://www.ncbi.nlm.nih.gov/pubmed/35982891
http://dx.doi.org/10.7150/ijbs.72367
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