title: Glioblastoma spheroids produce infiltrative gliomas in the rat brainstem.
abstract: OBJECTIVE
  Diffuse intrinsic pontine glioma (DIPG) is universally fatal without proven therapy other than radiation therapy for palliation. Representative animal models will play an essential role in the preclinical stage of future therapy development. To address the shortage of representative models, we created a novel infiltrative brainstem glioma model in rats based on glioblastoma spheroids.
  
  
  METHODS
  Cells dissociated from glioblastoma spheroids grown from surgical specimens were implanted into the brainstem of NIH nude rats. Animals were serially assessed clinically and radiographically with magnetic resonance imaging (MRI). Tumors were further characterized using histology, immunohistochemistry, and cytogenetics.
  
  
  RESULTS
  Tumor generation was successful in all animals receiving glioblastoma spheroid cells. The rats survived 17-25 weeks before severe symptoms developed. The tumors showed as diffuse hyperintense lesions on T2-weighted images. Histologically, they demonstrated cellular heterogeneity, and infiltrative and invasive features, with cells engorging vascular structures. The tumors were shown to comprise immature human origin glial tumor cells, with human epidermal growth factor receptor (EGFR) gene amplification and gain.
  
  
  CONCLUSIONS
  This study showed that cells from glioblastoma spheroids produced infiltrative gliomas in rat brainstem. The rat brainstem gliomas are radiographically and histologically accurate compared to DIPG. These tumors develop over several months that would allow sequential clinical and radiographic assessments of therapeutic interventions. This study demonstrated in principle the feasibility of developing patient-specific animal models based on putative cancer stem cells from biopsy or resection samples.
authors.affiliation: Department of Neurological Surgery, Weill Medical College of Cornell University, 525 East 68th Street, Box 99, New York, NY, 10065, USA. zhipingzhou@gmail.com.
authors.forename: Zhiping
authors.identifier: http://orcid.org/0000-0001-5774-3823
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: NeuroSpine Institute, Bedford, NH, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Luther
authors.affiliation: Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Ranjodh
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Neurological Surgery, Lenox Hill Hospital, Hofstra-NSLIJ School of Medicine, New York, NY, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Boockvar
authors.affiliation: Department of Neurological Surgery, Weill Medical College of Cornell University, 525 East 68th Street, Box 99, New York, NY, 10065, USA.|Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA.|Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Souweidane
authors.affiliation: Department of Neurological Surgery, Weill Medical College of Cornell University, 525 East 68th Street, Box 99, New York, NY, 10065, USA.|Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA.|Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D020295:Brain Stem Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D007519:Isoantigens / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009368:Neoplasm Transplantation; D020556:Neutrophil Infiltration / Q000502:physiology*; D051381:Rats; D011923:Rats, Nude; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007519:Isoantigens; C104384:neutrophil-specific antigen SH; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Brainstem glioma; Diffuse intrinsic pontine glioma; Glioblastoma spheroid; Infiltrative glioma