The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung

Adi F. Gazdar, Trisha K. Savage, Jane E. Johnson, Anton Berns, Julien Sage, R. Ilona Linnoila, David Macpherson, David G. Mcfadden, Anna Farago, Tyler Jacks, William D. Travis, Elisabeth Brambilla

Research output: Contribution to journalArticle

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Abstract

Introduction: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)553-564
Number of pages12
JournalJournal of Thoracic Oncology
Volume10
Issue number4
DOIs
StatePublished - Apr 30 2015

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Neuroendocrine Carcinoma
Pathology
Small Cell Lung Carcinoma
Lung
Neuroendocrine Cells
Neoplasms
Polyomavirus Transforming Antigens
Large Cell Carcinoma
Non-Small Cell Lung Carcinoma
Lymphatic Metastasis
Translational Medical Research
Neuroendocrine Tumors
Viral Tumor Antigens
Carcinoma in Situ
Mediastinum
Bronchi
Hematoxylin
Eosine Yellowish-(YS)
Hyperplasia
Blood Vessels

Keywords

  • Genetically engineered mouse models
  • Lung carcinoma
  • Neuroendocrine carcinomas
  • Non-small-cell lung cancer
  • Pathology
  • Small-cell lung carcinoma

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. / Gazdar, Adi F.; Savage, Trisha K.; Johnson, Jane E.; Berns, Anton; Sage, Julien; Linnoila, R. Ilona; Macpherson, David; Mcfadden, David G.; Farago, Anna; Jacks, Tyler; Travis, William D.; Brambilla, Elisabeth.

In: Journal of Thoracic Oncology, Vol. 10, No. 4, 30.04.2015, p. 553-564.

Research output: Contribution to journalArticle

Gazdar, AF, Savage, TK, Johnson, JE, Berns, A, Sage, J, Linnoila, RI, Macpherson, D, Mcfadden, DG, Farago, A, Jacks, T, Travis, WD & Brambilla, E 2015, 'The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung', Journal of Thoracic Oncology, vol. 10, no. 4, pp. 553-564. https://doi.org/10.1097/JTO.0000000000000459
Gazdar, Adi F. ; Savage, Trisha K. ; Johnson, Jane E. ; Berns, Anton ; Sage, Julien ; Linnoila, R. Ilona ; Macpherson, David ; Mcfadden, David G. ; Farago, Anna ; Jacks, Tyler ; Travis, William D. ; Brambilla, Elisabeth. / The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. In: Journal of Thoracic Oncology. 2015 ; Vol. 10, No. 4. pp. 553-564.
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AU - Savage, Trisha K.

AU - Johnson, Jane E.

AU - Berns, Anton

AU - Sage, Julien

AU - Linnoila, R. Ilona

AU - Macpherson, David

AU - Mcfadden, David G.

AU - Farago, Anna

AU - Jacks, Tyler

AU - Travis, William D.

AU - Brambilla, Elisabeth

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N2 - Introduction: 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. Conclusion: 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.

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