Patterns of Neoplasia in c-Mos Transgenic Mice and Their Relevance to Multiple Endocrine Neoplasia

We have previously described a neurological phenotype for transgenic mice carrying the c-Mos proto-oncogene. Pheochromocytomas and C-cell thyroid neoplasms occur in these transgenic lines in patterns that are similar to those seen in multiple endocrine neoplasia type 2 (MEN 2). Characterization of the pathological lesions via immunohistochemistry underscores similarities between MEN 2 and these transgenic mice. When transgenic mice that do not display the MEN 2 phenotype are crossed to a different background, the progeny display the MEN 2 phenotype. Thus the interaction of the background with the transgene is such that it can suppress tumor information. This observation bears special relevance to the human syndrome in that this model system may be used to study the question of penetrance of phenotype

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

IntroductionBecause 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.MethodsThe 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.ResultsThe 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.ConclusionThe 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

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

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. Key Words: Neuroendocrine carcinomas; Small-cell lung carcinoma; Lung carcinoma; Non–small-cell lung cancer; Genetically engineered mouse models; Patholog

Achaete-Scute Homologue-1 Tapers Neuroendocrine Cell Differentiation in Lungs after Exposure to Naphthalene

The basic helix-loop-helix transcription factor achaete-scute homologue-1 (ASH1) plays a critical role in regulating the neuroendocrine (NE) phenotype in normal and neoplastic lung. Transgenic (TG) mice that constitutively express human ASH1 (hASH1) under control of the Clara cell 10-kDa protein (CC10) promoter in non-NE airway lining cells display progressive epithelial hyperplasia and bronchiolar metaplasia or bronchiolization of the alveoli (BOA). However, little is known about the involvement of hASH1 in regeneration of the conducting airway. In this study, we investigated the impact of hASH1 on airway cell injury and repair in the TG mice following an intraperitoneal injection of naphthalene, which specifically ablates bronchiolar Clara cells and induces pulmonary NE cell hyperplasia. We discovered an overall attenuation of NE maturation coupled with increased proliferation in TG mice during post-naphthalene repair. In addition, BOA lesions revealed enhanced epithelial cell proliferation while preserving Clara cell markers CC10 and the principal naphthalene-metabolizing enzyme cytochrome P4502F2. These data suggest that ASH1 may play an important role in maintaining a progenitor phenotype that promotes renewal of both NE and epithelial cells. Moreover, ASH1 may propagate a stem cell microenvironment in BOA where epithelium becomes resistant to naphthalene toxicity