Establishment of a patient-derived orthotopic osteosarcoma mouse model.
BACKGROUND
Osteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue.


METHODS
Fresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin.


RESULTS
A primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established.


CONCLUSIONS
We report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS.
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. c.blattmann@klinikum-stuttgart.de.|Division of Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. c.blattmann@klinikum-stuttgart.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. c.blattmann@klinikum-stuttgart.de.
Claudia
C
Blattmann
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. m.thiemann@dkfz-heidelberg.de.|Division of Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.thiemann@dkfz-heidelberg.de.
Markus
M
Thiemann
Institute of Pathology, University of Heidelberg, Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de.
Albrecht
A
Stenzinger
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. eva.roth@med.uni-heidelberg.de.|Division of Radiooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. eva.roth@med.uni-heidelberg.de.
Eva K
EK
Roth
Department of Radiotherapy and Radiooncology, University of Heidelberg, Heidelberg, Germany. anne.dittmar@med.uni-heidelberg.de.|Institute of Pathology, University of Heidelberg, Heidelberg, Germany. anne.dittmar@med.uni-heidelberg.de.
Anne
A
Dittmar
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. hendrik.witt@med.uni-heidelberg.de.|Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. hendrik.witt@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. hendrik.witt@med.uni-heidelberg.de.
Hendrik
H
Witt
Department of Orthopedics, University of Heidelberg, Heidelberg, Germany. burkhard.lehner@med.uni-heidelberg.de.
Burkhard
B
Lehner
Department of Orthopedics, University of Heidelberg, Heidelberg, Germany. eva.renker@med.uni-heidelberg.de.
Eva
E
Renker
Core Facility, Small Animal Imaging Center, DKFZ, Heidelberg, Germany. m.jugold@dkfz-heidelberg.de.
Manfred
M
Jugold
Core Facility, Small Animal Imaging Center, DKFZ, Heidelberg, Germany. v.eichwald@dkfz-heidelberg.de.
Viktoria
V
Eichwald
Institute of Pathology, University of Heidelberg, Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.|National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. wilko.weichert@med.uni-heidelberg.de.
Wilko
W
Weichert
Institute of Pathology, University of Heidelberg, Heidelberg, Germany. p.huber@dkfz-heidelberg.de.
Peter E
PE
Huber
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.|National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. andreas.kulozik@med.uni-heidelberg.de.
Andreas E
AE
Kulozik
D000293:Adolescent; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D012008:Recurrence; D055114:X-Ray Microtomography