Genetic studies on lung tumor susceptibility and histogenesis in mice.

Abstract

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.ImagesFIGURE 2.FIGURE 3.FIGURE 3.

The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis

“…It should be noted that since C57BL/6J Lpar1 À/À mice are embryonically lethal (data not shown and ref. 16), Lpar1 À/À mice were bred and maintained on a mixed C57BL/6J/129 genetic background, which is known to be more susceptible to URE-induced carcinogenesis (24). In accordance, WT C57BL/6J/129 mice developed an increased number of ADs, as compared to WT C57BL/ 6J mice, upon URE administration (Fig.…”

Differential Transcriptomic Analysis of Spontaneous Lung Tumors in B6C3F1 Mice: Comparison to Human Non–Small Cell Lung Cancer

“…The National Toxicology Program’s (NTP) B6C3F1 mouse strain likely corresponds to the intermediate susceptible strain. This relative level of susceptibility to lung tumor development in the above mouse strains is also maintained in chemically induced lung tumor incidence (Malkinson 1991). …”

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

“…Focal adenomatous alveolar epithelial hyperplasia was observed at 17 months post-exposure in the terminal bronchiole/alveolar duct region (Sargent et al 2014). In humans, atypical adenomatous hyperplasia (AAH) is the form of primary bronchoalveolar hyperplasia considered to be preneoplastic (Foley et al 1991; Malkinson 1991; Brambilla et al 2001; Ress et al 2003; Sargent et al 2014; Pandiri 2015). For this reason, Sargent et al (2014) separated hyperplasia into general hyperplasia and focal adenomatous hyperplasia, which resembles human AAH and which was “characterized by an increase in the number of crowded alveolar epithelial cells that outlined contiguous alveolar septa in discrete, generally random locations” (Sargent et al 2014).…”