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Hepatology. 2020 Jan 3. doi: 10.1002/hep.31096. [Epub ahead of print]

Uncovering biological factors that regulate hepatocellular carcinoma growth using patient derived xenograft assays.

Author information

1
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
2
Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA, 75390, USA.
3
Department of Statistics, University of Michigan, Michigan Integrated Center for Health Analytics and Medical Prediction (MiCHAMP), Ann Arbor, MI, USA, Ann Arbor, MI, USA.
4
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
5
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
6
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
7
VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, MI, USA.
8
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine and Michigan Integrated Center for Health Analytics and Medical Prediction (MiCHAMP), Ann Arbor, MI, USA.

Abstract

Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient derived xenograft (PDX) models. In Asia, HCCs from hepatitis B virus patients have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NSG mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passagability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the US. PDX models preserved the histology and genetic features of parental tumors, and ultimately, 8 new models were usable for pre-clinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib and CCA PDXs were also highly sensitive to regorafenib. PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the US.

KEYWORDS:

Hepatocellular carcinoma; PDX; drug test; liver

PMID:
31899548
DOI:
10.1002/hep.31096

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