Key features of the environment promoting liver cancer in the absence of cirrhosis

Abstract The prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) is rising, even in the absence of cirrhosis. We aimed to develop a murine model that would facilitate further understanding of NAFLD-HCC pathogenesis. A total of 144 C3H/He mice...

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Autores principales:	Marco Youssef William Zaki, Ahmed Khairallah Mahdi, Gillian Lucinda Patman, Anna Whitehead, João Pais Maurício, Misti Vanette McCain, Despina Televantou, Sameh Abou-Beih, Erik Ramon-Gil, Robyn Watson, Charlotte Cox, Jack Leslie, Caroline Wilson, Olivier Govaere, John Lunec, Derek Austin Mann, Sirintra Nakjang, Fiona Oakley, Ruchi Shukla, Quentin Mark Anstee, Dina Tiniakos, Helen Louise Reeves
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c2466e2014fe4723915552556b300a2b
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spelling	oai:doaj.org-article:c2466e2014fe4723915552556b300a2b2021-12-02T15:10:50ZKey features of the environment promoting liver cancer in the absence of cirrhosis10.1038/s41598-021-96076-22045-2322https://doaj.org/article/c2466e2014fe4723915552556b300a2b2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96076-2https://doaj.org/toc/2045-2322Abstract The prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) is rising, even in the absence of cirrhosis. We aimed to develop a murine model that would facilitate further understanding of NAFLD-HCC pathogenesis. A total of 144 C3H/He mice were fed either control or American lifestyle (ALIOS) diet, with or without interventions, for up to 48 weeks of age. Gross, liver histology, immunohistochemistry (IHC) and RNA-sequencing data were interpreted alongside human datasets. The ALIOS diet promoted obesity, elevated liver weight, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD) and spontaneous HCC. Liver weight, fasting blood glucose, steatosis, lobular inflammation and lipogranulomas were associated with development of HCC, as were markers of hepatocyte proliferation and DNA damage. An antioxidant diminished cellular injury, fibrosis and DNA damage, but not lobular inflammation, lipogranulomas, proliferation and HCC development. An acquired CD44 phenotype in macrophages was associated with type 2 diabetes and NAFLD-HCC. In this diet induced NASH and HCC (DINAH) model, key features of obesity associated NAFLD-HCC have been reproduced, highlighting roles for hepatic steatosis and proliferation, with the acquisition of lobular inflammation and CD44 positive macrophages in the development of HCC—even in the absence of progressive injury and fibrosis.Marco Youssef William ZakiAhmed Khairallah MahdiGillian Lucinda PatmanAnna WhiteheadJoão Pais MaurícioMisti Vanette McCainDespina TelevantouSameh Abou-BeihErik Ramon-GilRobyn WatsonCharlotte CoxJack LeslieCaroline WilsonOlivier GovaereJohn LunecDerek Austin MannSirintra NakjangFiona OakleyRuchi ShuklaQuentin Mark AnsteeDina TiniakosHelen Louise ReevesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marco Youssef William Zaki Ahmed Khairallah Mahdi Gillian Lucinda Patman Anna Whitehead João Pais Maurício Misti Vanette McCain Despina Televantou Sameh Abou-Beih Erik Ramon-Gil Robyn Watson Charlotte Cox Jack Leslie Caroline Wilson Olivier Govaere John Lunec Derek Austin Mann Sirintra Nakjang Fiona Oakley Ruchi Shukla Quentin Mark Anstee Dina Tiniakos Helen Louise Reeves Key features of the environment promoting liver cancer in the absence of cirrhosis
description	Abstract The prevalence of obesity and non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) is rising, even in the absence of cirrhosis. We aimed to develop a murine model that would facilitate further understanding of NAFLD-HCC pathogenesis. A total of 144 C3H/He mice were fed either control or American lifestyle (ALIOS) diet, with or without interventions, for up to 48 weeks of age. Gross, liver histology, immunohistochemistry (IHC) and RNA-sequencing data were interpreted alongside human datasets. The ALIOS diet promoted obesity, elevated liver weight, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD) and spontaneous HCC. Liver weight, fasting blood glucose, steatosis, lobular inflammation and lipogranulomas were associated with development of HCC, as were markers of hepatocyte proliferation and DNA damage. An antioxidant diminished cellular injury, fibrosis and DNA damage, but not lobular inflammation, lipogranulomas, proliferation and HCC development. An acquired CD44 phenotype in macrophages was associated with type 2 diabetes and NAFLD-HCC. In this diet induced NASH and HCC (DINAH) model, key features of obesity associated NAFLD-HCC have been reproduced, highlighting roles for hepatic steatosis and proliferation, with the acquisition of lobular inflammation and CD44 positive macrophages in the development of HCC—even in the absence of progressive injury and fibrosis.
format	article
author	Marco Youssef William Zaki Ahmed Khairallah Mahdi Gillian Lucinda Patman Anna Whitehead João Pais Maurício Misti Vanette McCain Despina Televantou Sameh Abou-Beih Erik Ramon-Gil Robyn Watson Charlotte Cox Jack Leslie Caroline Wilson Olivier Govaere John Lunec Derek Austin Mann Sirintra Nakjang Fiona Oakley Ruchi Shukla Quentin Mark Anstee Dina Tiniakos Helen Louise Reeves
author_facet	Marco Youssef William Zaki Ahmed Khairallah Mahdi Gillian Lucinda Patman Anna Whitehead João Pais Maurício Misti Vanette McCain Despina Televantou Sameh Abou-Beih Erik Ramon-Gil Robyn Watson Charlotte Cox Jack Leslie Caroline Wilson Olivier Govaere John Lunec Derek Austin Mann Sirintra Nakjang Fiona Oakley Ruchi Shukla Quentin Mark Anstee Dina Tiniakos Helen Louise Reeves
author_sort	Marco Youssef William Zaki
title	Key features of the environment promoting liver cancer in the absence of cirrhosis
title_short	Key features of the environment promoting liver cancer in the absence of cirrhosis
title_full	Key features of the environment promoting liver cancer in the absence of cirrhosis
title_fullStr	Key features of the environment promoting liver cancer in the absence of cirrhosis
title_full_unstemmed	Key features of the environment promoting liver cancer in the absence of cirrhosis
title_sort	key features of the environment promoting liver cancer in the absence of cirrhosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c2466e2014fe4723915552556b300a2b
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Key features of the environment promoting liver cancer in the absence of cirrhosis

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