title: Establishment and characterization of esophageal squamous cell carcinoma patient-derived xenograft mouse models for preclinical drug discovery.
abstract: The purpose of this study was to establish and characterize patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mice for utilization in antitumor drug discovery. A total of 96 esophageal squamous cell carcinoma (ESCC) tissues from Chinese patients were transplanted subcutaneously into immunodeficient mice. Histology, EGFR, K-ras, B-raf, and PIK3CA mutations, and HER2 gene amplifications were analyzed in both patient tumors and mouse xenograft tissues using immunohistochemistry, mutant-enriched liquid chip sequencing and fluorescence in situ hybridization assays, respectively. Furthermore, in vivo efficacy studies using five PDECX mice harboring a variety of genetic aberrations were performed using the chemotherapy agents 5-fluorouracil (5-FU) and cisplatin. Thirty-seven PDECX mouse models were successfully established in immunodeficient mice. Pathological analysis revealed similar histological architecture and degrees of differentiation between patient ESCC and xenografted tumors. No mutations were identified in EGFR, K-ras, and B-raf genes in either xenograft models or patient ESCC tissues. In contrast, PIK3CA gene mutations were detected in 12.5% (12/96) ESCC patients and 18.9% (7/37) PDECX models. Interestingly, patient ESCC tissues exhibiting HER2 overexpression or gene amplification were unable to survive in immunodeficient mice. Further analysis showed that PDECX models carrying HER2 2+ expression had no response to 5-FU/cisplatin, compared with HER2-negative models. In conclusion, a panel of PDECX mouse models, which include PIK3CA mutant and HER2-positive models, was established and characterized thus mimicking the current clinical genetic setting of esophageal carcinoma. The sensitivity of HER2-negative ESCC models to chemotherapy supports stratification approaches in the treatment of esophageal carcinoma patients and warrants further investigation of the impact of PI3KCA on treatment response.
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Dongxian
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lv
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Ge
authors.affiliation: Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Songtao
authors.initials: S
authors.lastname: Xu
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Leon
authors.initials: L
authors.lastname: Li
authors.affiliation: Innovation Center China, AstraZeneca Global R&D, Zhangjiang Hi-Tech Park, Shanghai, People's Republic of China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yingyong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Thorax Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002681:China; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; C503859:PI3KCA protein, human; C508053:ERBB2 protein, human