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.
Highlights
Gastric carcinoma (GC) is the third most common cancer worldwide and is the most frequent cancer diagnosed in East Asian countries [1]
Histological hematoxylin and eosin (H&E) assessment was performed by pathologist for all 207 GC patient tumors and 32 established patient-derived gastric cancer xenograft (PDGCX) models. 16 models were classified as intestinal subtype, 11 were diffuse subtype and 5 were mixed subtype
To explore the genetic characteristics of the established PDGCX models, we focused on analysis of well-characterized driver oncogenes in GC including: the ERBB family members (ERBB1, ERBB2 & ERBB3), PTEN, FGFR2 and MET as listed in S1 Table
Summary
Gastric carcinoma (GC) is the third most common cancer worldwide and is the most frequent cancer diagnosed in East Asian countries [1]. Despite recent progress in earlier diagnosis and improved therapeutic regimens, many patients still eventually develop advanced disease and have poor clinical outcomes. With regard to standard chemotherapy, limited efficacy has spurred research into targeted therapies designed to block signaling via molecular pathways known to be important for gastric tumorigenesis [3, 4]. Within the drug development process, evaluation of preclinical efficacy with relevant in vivo models is an important checkpoint before moving the drug forward into human clinical studies. One of our research goals is to establish appropriate preclinical models which as accurately as possible represent the complexity of human GC and provide predictive power
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