Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents

Gao, Qiang; Wang, Zhi Chao; Duan, Meng; Lin, Yi Hui; Zhou, Xue; Worthley, Daniel L.; Wang, Xiaoying; Niu, Gang; Xia, Yuchao; Deng, Minghua; Liu, Long Zi; Shi, Jie; Yang, Liu Xiao; Zhang, Shu; Ding, Zheng; Zhou, Jian; Liang, Chun; Cao, Yang; Xiong, Lei; Xi, Ruibin; Shi, Yongyong; Fan, Jia

doi:10.1053/j.gastro.2016.09.008

Cited by 115 publications

(80 citation statements)

References 45 publications

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“…Furthermore, the intratumour heterogeneity of HCC may result in a more significant discrepancy between gene amplification and mRNA expression. Using multiregional whole‐exome sequencing, copy number analysis, and high‐throughput screening for HBV‐related HCCs, Gao et al reported that 53.8% of driver genetic alterations are subclonal events . Similarly, Schulze et al demonstrated that genetic alterations in FGF3 , FGF4 , FGF19 and CCND1 are prone to occur at more advanced stages in HCC, suggesting that these genetic alterations appear in subclonal cell populations.…”

Section: Discussionmentioning

confidence: 99%

Klotho‐beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma

Lin

Hsu

Jeng

et al. 2019

Liver International

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Background and Aims Fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) signalling play critical roles in hepatocarcinogenesis. This study explored the potential of FGF19‐ and FGFR4‐related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC). Methods We examined the mRNA expressions of FGF19, FGFR4, klotho‐beta (KLB), cyclin D1 (CCND1) and FGF4 in 151 surgically resected, primary unifocal HCCs through quantitative real‐time polymerase chain reaction. Generalized additive models were fitted to detect nonlinear effects of continuous covariates and define thresholds of biomarker expressions. Univariate and multivariate analyses were performed to evaluate prognostic values of these biomarkers for tumour recurrence and patient survival. Results Overexpression of FGF19, FGFR4, KLB, CCND1 and FGF4 mRNA was detected in 40%, 32%, 26%, 15% and 35% of 151 tumours respectively. ETR was the strongest prognostic factor predicting worse overall survival (hazard ratio [HR], 5.678; 95% confidence interval, 3.7‐8.713; P < 0.001). Furthermore, we revealed that mRNA expression levels of KLB (HR, 3.857; P = 0.021) and FGF19 (HR, 3.248; P = 0.017) were significantly associated with the occurrence of ETR. Conclusions Frequent overexpression of FGF19/FGFR4‐related biomarkers was detected in resectable HCC. Expression levels of KLB and FGF19 may determine patient survival outcomes through their effects on ETR.

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Section: Discussionmentioning

confidence: 99%

Klotho‐beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma

Lin

Hsu

Jeng

et al. 2019

Liver International

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“…Cancer cell lines are valuable in vitro models for analyzing genetic heterogeneity within tumors and for screening pharmacologic agents for anticancer assessment . Recently, on the basis of transcriptome meta‐analysis of 603 clinical HCC tissues, HCC cell lines have been classified into subtypes .…”

Section: Introductionmentioning

confidence: 99%

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Augello

Emma

Cusimano

et al. 2018

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter‐ and intra‐tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well‐characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but its role in hepatocarcinogenesis remains unclear. Here, we analyzed HSP90 expression in primary human HCC tissues and evaluated the antitumor effects of AUY922 in vitro as well as in vivo. HSP90 expression was significantly higher in HCC tissues than in cirrhotic peritumoral liver tissues. AUY922 treatment reduced the cell proliferation and viability of HCC cells in a dose‐dependent manner, but did not do so for normal human primary hepatocytes. AUY922 treatment led to the upregulation of HSP70 and the simultaneous depletion of HSP90 client proteins. In addition, in a cell type‐dependent manner, treatment induced either both caspase‐dependent β‐catenin cleavage and the upregulation of p53, or Mcl‐1 expression, or NUPR1 expression, which contributed to the increased efficacy of, or resistance to, treatment. Finally, in vivo AUY922 inhibited tumor growth in a xenograft model. In conclusion, HSP90 is a promising therapeutic target in HCC, and AUY922 could be a drug candidate for its treatment.

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“…11,12 Furthermore, Gao et al recently generated several PDCL from the same tumors to dissect intrahepatic tumor heterogeneity in HCC. 13 This and other studies in lung cancer also successfully applied PDCL for drug discovery, prediction of therapy response and selection of effective drug combinations. 14 Overall, results of these elegant studies confirm the similarity in key morphological and molecular features for PDCL and matched primary cancers and support their usefulness in individualized, patient-specific models for treatment evaluation and drug response testing.…”

Section: Introductionmentioning

confidence: 91%

“…Furthermore, Gao et al . recently generated several PDCL from the same tumors to dissect intrahepatic tumor heterogeneity in HCC . This and other studies in lung cancer also successfully applied PDCL for drug discovery, prediction of therapy response and selection of effective drug combinations .…”

Section: Introductionmentioning

confidence: 97%

Application of patient‐derived liver cancer cells for phenotypic characterization and therapeutic target identification

Castven

Becker

Czauderna

et al. 2018

Intl Journal of Cancer

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Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long‐term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were performed using next‐generation sequencing (NGS). Key oncogenic alterations were identified by targeted NGS and cell lines carrying potentially actionable mutations were treated with corresponding specific inhibitors. PDCL fully resembled morphological features of the primary cancers in vitro and in vivo over extended period in culture. Genomic alterations as well as transcriptome profiles showed high similarity with primary tumors and remained stable during long‐term culturing. Targeted‐NGS confirmed that key oncogenic mutations such as TP53, KRAS, CTNNB1 as well as actionable mutations (e.g. MET, cKIT, KDR) were highly conserved in PDCL and amenable for individualized therapeutic approaches. Integrative genomic and transcriptomic approaches further demonstrated that PDCL more closely resemble molecular and prognostic features of PLC than established cell lines and are valuable tool for direct target evaluation. Our integrative analysis demonstrates that PDCL represents refined model for discovery of relevant molecular subgroups and exploration of precision medicine approaches for the treatment of this deadly disease.

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Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents

Cited by 115 publications

References 45 publications

Klotho‐beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma

Klotho‐beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Application of patient‐derived liver cancer cells for phenotypic characterization and therapeutic target identification

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