Abstract
Constitutive expression of human achaete-scute homolog-1 (hASH1) alone or in combination with Simian virus 40 (SV40) large T antigen (TAg) under the Clara cell 10-kDa secretory protein (CC10) promoter results in bronchiolization of alveoli and enhanced tumorigenesis, respectively. A novel morphometric system composed of series of fixed distance concentric rings originating at the bronchioloalveolar junction was used to determine spatial growth patterns. hASH1 mice exhibited progressive airway epithelial hyperplasia near this junction, and minimal changes further away in the alveolar compartment. TAg animals shared this increase, but exhibited variable distance-dependent growth. By 2 months TAg/hASH1 animals showed highly increased growth at all points measured. Remarkably, TAg/hASH1 animals expressed both CC10 and extensive neuroendocrine differentiation in airways and tumors. The results suggest that these transgenic mice provide a useful model with many similarities to human lung carcinogenesis, which originates in airway epithelium, and often reveals neuroendocrine differentiation.
Publication types
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Comparative Study
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Evaluation Study
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor / metabolism
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Bronchi / metabolism
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Bronchi / pathology
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Carcinoma, Neuroendocrine / genetics
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Carcinoma, Neuroendocrine / metabolism
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Carcinoma, Neuroendocrine / pathology*
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DNA Primers / chemistry
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Disease Models, Animal*
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Humans
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Hyperplasia / pathology
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Image Processing, Computer-Assisted
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Immunoenzyme Techniques
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Lung / metabolism
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Lung / pathology*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Metaplasia / pathology
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Mice
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Mice, Transgenic*
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Proteins / genetics*
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Proteins / metabolism
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Pulmonary Alveoli / metabolism
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Pulmonary Alveoli / pathology
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RNA, Neoplasm / analysis
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Uteroglobin*
Substances
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ASCL1 protein, human
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Antigens, Polyomavirus Transforming
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Ascl1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor
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DNA Primers
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DNA-Binding Proteins
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Proteins
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RNA, Neoplasm
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SCGB1A1 protein, human
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Scgb1a1 protein, mouse
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Transcription Factors
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Uteroglobin