Genetic studies on lung tumor susceptibility and histogenesis in mice.
The probability that a mouse develops a pulmonary tumor, as well as the structure of that tumor, are dependent on several genes. Three pulmonary adenoma susceptibility (pas) genes predispose some inbred strains to develop lung tumors, even in the absence of carcinogen exposure, and cause others to be resistant. One pas gene is K-ras, which may also be overexpressed in these tumors in a mutated form capable of transforming cells. Mice with activated Ha-ras transgenes override the resistant pas alleles and are born with lung cancer. Susceptible strains have a higher turnover rate of alveolar type II and bronchiolar Clara cells, those cells from which lung tumors arise, than more resistant strains. A high precursor cell turnover rate correlates with a propensity to neoplasia in other animal models as well, possibly due to low concentrations of endogenous growth regulatory molecules such as corticosterone and protein kinase C (PKC). Neoplastic lung epithelial cells are relatively resistant to glucocorticoids and have low PKC levels. A set of genes other than the pas genes governs the response to tumor modulation by butylated hydroxytoluene (BHT). The genes that determine whether lung tumor multiplicity is enhanced by chronic BHT exposure may regulate the ability to hydroxylate BHT at a tert-butyl position to form BHT-OH, a metabolite with greater tumor-promoting potency than BHT. Inbred and recombinant inbred strain variations in adenoma growth patterns indicate that another set of genes, which we have designated pah for pulmonary adenoma histogenesis, may determine which cell type becomes neoplastic and whether adenomas will undergo malignant conversion.
Malkinson
A M
AM
Molecular Toxicology and Environmental Health Program, School of Pharmacy, University of Colorado, Boulder, 80309-0297.
D000483:Alleles; D000818:Animals; D002084:Butylated Hydroxytoluene / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003043:Cocarcinogenesis; D003537:Cystadenoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D005938:Glucocorticoids / Q000494:pharmacology; D006824:Hybridization, Genetic; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011519:Proto-Oncogenes; D011650:Pulmonary Alveoli / Q000473:pathology; D013234:Stem Cells / Q000166:cytology; D014520:Urethane
D005938:Glucocorticoids; D009363:Neoplasm Proteins; D002084:Butylated Hydroxytoluene; D014520:Urethane; D011493:Protein Kinase C