title: Patient-Derived Gastric Carcinoma Xenograft Mouse Models Faithfully Represent Human Tumor Molecular Diversity.
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.
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Shuqiong
authors.initials: S
authors.lastname: Fan
authors.affiliation: Research and Development Information, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Meizhuo
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Fu
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Ni
authors.affiliation: Asia & Emerging Markets iMed, AstraZeneca R&D, Shanghai, P.R. China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D013274:Stomach Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor