Genomics

Dataset Information

52

Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma


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. Overall design: In this study, we investigate and compare the effects of two factors (cell lines vs. patient explants; ectopic vs. orthotopic) on gene expression profiles of HCC tumors. We hypothesized that differences would be observed in gene expression between ectopically and orthotopically transplanted tumors, and also between fresh patient-explanted tumors and established commercial cell lines. The similarities or differences between the sites and tumor types could potentially direct areas for future study.

INSTRUMENT(S): [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array

SUBMITTER: Yonghui Wu  

PROVIDER: GSE72981 | GEO | 2015-11-17

SECONDARY ACCESSION(S): PRJNA295516

REPOSITORIES: GEO

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Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma.

Wang Weining W   Iyer N Gopalakrishna NG   Tay Hsien Ts'ung HT   Wu Yonghui Y   Lim Tony K H TK   Zheng Lin L   Song In Chin IC   Kwoh Chee Keong CK   Huynh Hung H   Tan Patrick O B PO   Chow Pierce K H PK  

BMC cancer 20151031


<h4>Background</h4>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 profil  ...[more]

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