title: Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.
abstract: The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Wayne State University, School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Lorin
authors.initials: L
authors.lastname: Dodbiba
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Teichman
authors.affiliation: Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Fleet
authors.affiliation: University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Henry
authors.initials: H
authors.lastname: Thai
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Radiation Oncology (Maastro), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.
authors.forename: Maud H W
authors.initials: MH
authors.lastname: Starmans
authors.affiliation: Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Roya
authors.initials: R
authors.lastname: Navab
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Anatomical Pathology, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Hala
authors.initials: H
authors.lastname: Girgis
authors.affiliation: Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Lawson
authors.initials: L
authors.lastname: Eng
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Espin-Garcia
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Shen
authors.affiliation: Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Bizhan
authors.initials: B
authors.lastname: Bandarchi
authors.affiliation: Department of Anatomical Pathology, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Joerg
authors.initials: J
authors.lastname: Schwock
authors.affiliation: Ontario Cancer Institute, Toronto, ON, Canada; University Health Network, Princess Margaret Hospital, Toronto, ON, Canada; Department of Anatomical Pathology, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: University Health Network, Princess Margaret Hospital, Toronto, ON, Canada; Department of Anatomical Pathology, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Hala
authors.initials: H
authors.lastname: El-Zimaity
authors.affiliation: Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Sandy D
authors.initials: SD
authors.lastname: Der
authors.affiliation: Department of Biostatistics, Princess Margaret Hospital, Toronto, Canada; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Division of Thoracic Surgery, Toronto General Hospital, Toronto, ON, Canada.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Darling
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Cancer Institute, Toronto, ON, Canada.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Ailles
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Cancer Institute, Toronto, ON, Canada; Division of Epidemiology, Dalla Lana School of Public Health, Toronto, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004943:Esophagogastric Junction / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
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