Patient-Derived Gastric Carcinoma Xenograft Mouse Models Faithfully Represent Human Tumor Molecular Diversity

PLoS One. 2015 Jul 28;10(7):e0134493. doi: 10.1371/journal.pone.0134493. eCollection 2015.

Abstract

Patient-derived cancer xenografts (PDCX) generally represent more reliable models of human disease in which to evaluate a potential drugs preclinical efficacy. However to date, only a few patient-derived gastric cancer xenograft (PDGCX) models have been reported. In this study, we aimed to establish additional PDGCX models and to evaluate whether these models accurately reflected the histological and genetic diversities of the corresponding patient tumors. By engrafting fresh patient gastric cancer (GC) tissues into immune-compromised mice (SCID and/or nude mice), thirty two PDGCX models were established. Histological features were assessed by a qualified pathologist based on H&E staining. Genomic comparison was performed for several biomarkers including ERBB1, ERBB2, ERBB3, FGFR2, MET and PTEN. These biomarkers were profiled to assess gene copy number by fluorescent in situ hybridization (FISH) and/or protein expression by immunohistochemistry (IHC). All 32 PDGCX models retained the histological features of the corresponding human tumors. Furthermore, among the 32 models, 78% (25/32) highly expressed ERBB1 (EGFR), 22% (7/32) were ERBB2 (HER2) positive, 78% (25/32) showed ERBB3 (HER3) high expression, 66% (21/32) lost PTEN expression, 3% (1/32) harbored FGFR2 amplification, 41% (13/32) were positive for MET expression and 16% (5/32) were MET gene amplified. Between the PDGCX models and their parental tumors, a high degree of similarity was observed for FGFR2 and MET gene amplification, and also for ERBB2 status (agreement rate = 94~100%; kappa value = 0.81~1). Protein expression of PTEN and MET also showed moderate agreement (agreement rate = 78%; kappa value = 0.46~0.56), while ERBB1 and ERBB3 expression showed slight agreement (agreement rate = 59~75%; kappa value = 0.18~0.19). ERBB2 positivity, FGFR2 or MET gene amplification was all maintained until passage 12 in mice. The stability of the molecular profiles observed across subsequent passages within the individual models provides confidence in the utility and translational significance of these models for in vivo testing of personalized therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism*
  • Female
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization, Fluorescence
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology*
  • Neoplasm Staging
  • Prognosis
  • Stomach Neoplasms / classification*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor

Grants and funding

This study is fully funded by AstraZeneca. To clarify, AstraZeneca authors were fully involved in study design, data collection and analysis, decision to publish, or preparation of the manuscript.