Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Wang W

PROVIDER: S-EPMC4628260 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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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]

PMID: 26520397

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Project description: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.

Project description:ObjectiveThis study aimed to synthesize the available knowledge of identifying hepatocellular carcinoma (HCC) symptoms and symptom clusters in patients with HCC and instruments used for these assessments to maximize symptom management.MethodsWhittemore and Knafl's integrative review method was employed to guide a systematic search for literature in five databases (PubMed, ScienceDirect, Scopus, CINAHL, and ThaiJO). The retrieved articles were limited to those which were peer-reviewed, published between 2005 and 2022, and had English abstracts. All of identified studies were screened, extracted, and analyzed independently by two researchers.ResultFourteen articles were included in this review. They were grouped into three themes: symptoms, symptom assessment, and symptom clusters of HCC patients. Fatigue, lack of energy, stomach or abdominal pain/distension, loss of appetite, change in taste, sleep disturbance, distress, and sadness are the most prevalent symptoms reported in HCC patients. The different concurrent symptoms are related to the stage and treatment. Five types of symptom assessment instruments were commonly used (symptoms-specific HCC, general cancer symptom, measuring non-symptom constructs, measuring specific symptoms, such as fatigue, sleep disturbance, anxiety, and depression, and symptom assessment with clinical examination). Furthermore, the symptom clusters in HCC patients were classified into five categories: 1) pain-related symptoms, 2) gastrointestinal symptoms, 3) neuropsychological symptom clusters and sensory symptoms, 4) liver dysfunction-related symptom clusters, and 5) others (including sickness symptom clusters, fatigue clusters, location pain symptoms, and asymptomatic or symptomatic).ConclusionThe findings of this review add to the body of knowledge on symptoms, symptom assessment, and symptom clusters in patients with HCC. Despite a variety of instruments being available, none covers all symptoms experienced by HCC patients. It is recommended that future studies should include larger and more homogenous samples to evaluate assessment instruments more precisely, avoid ambiguity in classifying symptoms into symptom clusters, and increase the effectiveness of symptom management.

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

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

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