Morphometric analysis of CC10-hASH1 transgenic mouse lung: a model for bronchiolization of alveoli and neuroendocrine carcinoma.
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.
Linnoila
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Cell and Cancer Biology Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institute of Health, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, USA. il17h@nih.gov
Sahu
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Miki
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Ball
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DeMayo
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D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014598:Uteroglobin
D000952:Antigens, Polyomavirus Transforming; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011506:Proteins; D012334:RNA, Neoplasm; D014157:Transcription Factors; D014598:Uteroglobin; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse