title: The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung.
abstract: BACKGROUND
  Because small-cell lung carcinomas (SCLC) are seldom resected, human materials for study are limited. Thus, genetically engineered mouse models (GEMMs) for SCLC and other high-grade lung neuroendocrine (NE) carcinomas are crucial for translational research.
  
  
  METHODS
  The pathologies of five GEMMs were studied in detail and consensus diagnoses reached by four lung cancer pathology experts. Hematoxylin and Eosin and immunostained slides of over 100 mice were obtained from the originating and other laboratories and digitalized. The GEMMs included the original Rb/p53 double knockout (Berns Laboratory) and triple knockouts from the Sage, MacPherson, and Jacks laboratories (double knockout model plus loss of p130 [Sage laboratory] or loss of Pten [MacPherson and Jacks laboratories]). In addition, a GEMM with constitutive co-expression of SV40 large T antigen and Ascl1 under the Scgb1a1 promoter from the Linnoila laboratory were included.
  
  
  RESULTS
  The lung tumors in all of the models had common as well as distinct pathological features. All three conditional knockout models resulted in multiple pulmonary tumors arising mainly from the central compartment (large bronchi) with foci of in situ carcinoma and NE cell hyperplasia. They consisted of inter- and intra-tumor mixtures of SCLC and large-cell NE cell carcinoma in varying proportions. Occasional adeno- or large-cell carcinomas were also seen. Extensive vascular and lymphatic invasion and metastases to the mediastinum and liver were noted, mainly of SCLC histology. In the Rb/p53/Pten triple knockout model from the MacPherson and Jacks laboratories and in the constitutive SV40/T antigen model many peripherally arising non-small-cell lung carcinoma tumors having varying degrees of NE marker expression were present (non-small-cell lung carcinoma-NE tumors). The resultant histological phenotypes were influenced by the introduction of specific genetic alterations, by inactivation of one or both alleles of specific genes, by time from Cre activation and by targeting of lung cells or NE cell subpopulations.
  
  
  CONCLUSIONS
  The five GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. They represent one of the most advanced forms of currently available GEMM models for the study of human cancer.
authors: *Hamon Center for Therapeutic Oncology Research and Department of Pathology, UT Southwestern Medical Center, Dallas, TX; †Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX; ‡Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands; §Departments of Pediatrics and Genetics, Stanford University, Stanford, CA; ‖Center for Cancer Research, National Cancer Institute, Bethesda, MD; ¶Division of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; #David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142; **Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; and ††Departementd'Anatomie et Cytologie Pathologiques, INSERM Unit 823, Centre Hospitalier Universitaire Albert Michallon, and Institut Albert Bonniot University, Grenoble, France.
authors: Adi F
authors: AF
authors: Gazdar
authors: Trisha K
authors: TK
authors: Savage
authors: Jane E
authors: JE
authors: Johnson
authors: Anton
authors: A
authors: Berns
authors: Julien
authors: J
authors: Sage
authors: R Ilona
authors: RI
authors: Linnoila
authors: David
authors: D
authors: MacPherson
authors: David G
authors: DG
authors: McFadden
authors: Anna
authors: A
authors: Farago
authors: Tyler
authors: T
authors: Jacks
authors: William D
authors: WD
authors: Travis
authors: Elisabeth
authors: E
authors: Brambilla
mesh_terms: D000818:Animals; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000473:pathology*; D005818:Genetic Engineering / Q000379:methods*; D008168:Lung / Q000648:ultrastructure*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009374:Neoplasms, Experimental; D014407:Tumor Cells, Cultured