Abstract 2412: Molecular characterization of hepatocellular carcinoma (HCC) patient-derived explant models

Abstract

Recent evidence suggested that cancer patient-derived explant mouse models can maintain certain pathological and molecular features of the original diseases/patients, which offers potential opportunities for testing “personalized medicine” preclinically. We have established over 20 HCC explant models by directly implanting fresh tumor tissues derived from HCC patients into immunodeficient mice. To assess whether these HCC models would represent HCC clinical characteristics and individual patient diversity, we have compared the molecular profiles of these xenografts with their corresponding patient tissues (F0). This included gene copy variation by aCGH, mRNA expression by Affymetrix and gene mutations as well as protein expressions by immunohistochemistry. In addition, we also assessed the stability of the molecular profiles of various models by comparing different passages (F1-F10). Analysis of the data revealed that the xenograft tumors maintain fundamental genotypic features of the original patients, which recapitulate the genetic diversity of the HCC. The assessment on the stability of molecular profiles of individual model based on Pearson correlation coefficient (r) of aCGH data from different passages (F1-F10) suggests that those HCC models are very stable across passages (r > 0.8). In addition, no dramatic changes of the known molecular and histological features were observed throughout serial passages. AFP mRNA expressions of various models by Affymetrix are very different and mirror patient clinical data very well. Amplification of myc and cycline D1 and deletion of DLC1 and FHIT were detected in different individual models, as well as in corresponding patient HCC tissues, and those aberrations are consistent throughout the passages within various individual model. Furthermore, passages of the tumors in successive cohorts of mice did not change their sensitivity to sorafenib. In summary, we have developed preclinical HCC patient-derived explant models that can be used to further understand the disease and develop mechanism-based anti-cancer drugs for treatment of HCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2412. doi:10.1158/1538-7445.AM2011-2412

Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: Potential prospects for combined targeted therapeutics

“…The analyses of gene copy number, gene mutation, mRNA expression, and protein expression profiles demonstrated that transplanted tumors preserve the genotypic alterations of the original tumors. Consistent with the concept of oncogene addiction and tumor suppressor hypersensitivity, amplification of MYC and cyclin D1 oncogenes and deletion of DLC1 and FHIT TSGs were detected in different individual models, as well as in corresponding patients’ HCC tissues (149). …”