title: Preclinical models for neuroblastoma: establishing a baseline for treatment.
abstract: BACKGROUND
  Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.
  
  
  RESULTS
  Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.
  
  
  CONCLUSIONS
  The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer.
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Tal
authors.initials: T
authors.lastname: Teitz
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Stanke
authors.forename: Sara
authors.initials: S
authors.lastname: Federico
authors.forename: Cori L
authors.initials: CL
authors.lastname: Bradley
authors.forename: Rachel
authors.initials: R
authors.lastname: Brennan
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Jan
authors.initials: J
authors.lastname: Sedlacik
authors.forename: Madoka
authors.initials: M
authors.lastname: Inoue
authors.forename: Ziwei M
authors.initials: ZM
authors.lastname: Zhang
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Hillenbrand
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Christopher
authors.initials: C
authors.lastname: Calabrese
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009423:Nervous System Neoplasms / Q000235:genetics / Q000473:pathology*; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis