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Title: Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma
Authors: Wang, Weining
Iyer, N. Gopalakrishna
Tay, Hsien Ts’ung
Wu, Yonghui
Lim, Tony K. H.
Zheng, Lin
Song, In Chin
Kwoh, Chee Keong
Huynh, Hung
Tan, Patrick O. B.
Chow, Pierce K. H.
Keywords: Orthotopic
HepG2 cell line
Hepatocellular carcinoma
Issue Date: 2015
Source: Wang, W., Iyer, N. G., Tay, H. T., Wu, Y., Lim, T. K. H., Zheng, L., et al. (2015). Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma. BMC Cancer, 15, 828-.
Series/Report no.: BMC Cancer
Abstract: Background: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Methods: Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. Results: PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. Conclusions: The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long-held notion that orthotopic PDX model is the gold standard preclinical model for HCC.
ISSN: 1471-2407
DOI: 10.1186/s12885-015-1814-8
Schools: School of Computer Engineering 
Rights: © 2015 Wang et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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