Journal Article

3-Methylcholanthrene triggers the differentiation of alveolar tumor cells from canine bronchial basal cells and an altered <i>p53</i> gene promotes their clonal expansion

Ank A.W. TenHave-Opbroek, Xu-Bao Shi and Paul H. Gumerlock

in Carcinogenesis

Volume 21, issue 8, pages 1477-1484
Published in print August 2000 | ISSN: 0143-3334
Published online August 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.8.1477
3-Methylcholanthrene triggers the differentiation of alveolar tumor cells from canine bronchial basal cells and an altered p53 gene promotes their clonal expansion

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Alveolar type II cells arising in canine bronchial autografts following exposure to 3-methylcholanthrene (MCA) give rise to carcinomas of varying glandular and squamous growth patterns. To study the role of the tumor suppressor gene p53 in this process, sections from progressive lesions were immunostained for p53 protein; microdissected regions were screened for p53 mutations. Adjacent sections were examined for type II cell expression [cuboid cell shape, large roundish nucleus, cytoplasmic staining for surfactant protein A (SP-A)] and proliferating cell nuclear antigen expression. Evidence for an altered p53 function (nuclear staining, missense mutations) was found in most carcinomas of all histologic types and in all grades of bronchial dysplasia, but not in hyperplastic or normal bronchial epithelium. It was primarily associated with the hyperplastic type II cell populations present in the basal zone of the lesions. In addition, we found SP-A staining in hyperplastic (but not in normal) bronchial basal cells. These data suggest that MCA initiates type II cell differentiation through phenotypic selection (basal cells). Inactivation of the p53 gene promotes the clonal expansion of the type II cells into discernible populations of (squamous or glandular) alveolar tumor cells. This in vivo study is the first to show that p53 is involved in a specific pathway leading to bronchogenic carcinoma.

Keywords: H&E, hematoxylin and eosin; MCA, 3-methylcholanthrene; PCNA, proliferating cell nuclear antigen; SBA, subcutaneous bronchial autograft; SP-A, surfactant protein A; SSCP, single-strand conformation polymorphism.

Journal Article.  5810 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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