title: The next generation of orthotopic thyroid cancer models: immunocompetent orthotopic mouse models of BRAF V600E-positive papillary and anaplastic thyroid carcinoma.
abstract: BACKGROUND
  While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient mice. Genetically engineered models of papillary and undifferentiated (anaplastic) thyroid carcinoma (PTC and ATC) are immunocompetent; however, slow and stochastic tumor development hinders high-throughput testing. Novel models of PTC and ATC in which tumors arise rapidly and synchronously in immunocompetent mice would facilitate the investigation of novel therapeutics and approaches.
  
  
  METHODS
  We characterized and utilized mouse cell lines derived from PTC and ATC tumors arising in genetically engineered mice with thyroid-specific expression of endogenous Braf(V600E/WT) and deletion of either Trp53 (p53) or Pten. These murine thyroid cancer cells were transduced with luciferase- and GFP-expressing lentivirus and implanted into the thyroid glands of immunocompetent syngeneic B6129SF1/J mice in which the growth characteristics were assessed.
  
  
  RESULTS
  Large locally aggressive thyroid tumors form within one week of implantation. Tumors recapitulate their histologic subtype, including well-differentiated PTC and ATC, and exhibit CD3+, CD8+, B220+, and CD163+ immune cell infiltration. Tumor progression can be followed in vivo using luciferase and ex vivo using GFP. Metastatic spread is not detected at early time points.
  
  
  CONCLUSIONS
  We describe the development of the next generation of murine orthotopic thyroid cancer models. The implantation of genetically defined murine BRAF-mutated PTC and ATC cell lines into syngeneic mice results in rapid and synchronous tumor formation. This model allows for preclinical investigation of novel therapeutics and/or therapeutic combinations in the context of a functional immune system.
authors.affiliation: 1 Department of Surgery, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanden Borre
authors.forename: David G
authors.initials: DG
authors.lastname: McFadden
authors.forename: Viswanath
authors.initials: V
authors.lastname: Gunda
authors.forename: Peter M
authors.initials: PM
authors.lastname: Sadow
authors.forename: Shohreh
authors.initials: S
authors.lastname: Varmeh
authors.forename: Maria
authors.initials: M
authors.lastname: Bernasconi
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Sareh
authors.initials: S
authors.lastname: Parangi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016158:Genes, p53; D006801:Humans; D007121:Immunocompetence; D064596:Isografts; D020935:MAP Kinase Signaling System; D051379:Mice; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse