Induction and Modulation of Lung Tumors: Genomic and Transcriptional Alterations in Cigarette Smoke-exposed Mice

Abstract

Cigarette smoke plays a major role in the epidemiology of lung cancer, and smoke components have extensively been investigated in carcinogenicity and chemoprevention studies in experimental animals. However, it is much more difficult to reproduce the tumorigenicity of the whole complex mixture in preclinical models. The authors review here some results obtained in their laboratories, dealing with the induction of lung tumors, and genomic and transciptional alterations in smoke-exposed mice. The authors were successful in inducing lung tumors in 4 strains of mice exposed whole-body to environmental cigarette smoke, including Swiss albino, A/J, SKH-1 hairless, and p53 mutant (UL533 x A/J)F1 mice. However, the tumorigenic response was rather weak in all strains. Much more intense were the smoke-induced alterations of a variety of intermediate biomarkers, such as cytogenetic end points in pulmonary alveolar macrophages, bone marrow and peripheral blood erythrocytes; apoptosis, p53 oncoprotein, and proliferating cell nuclear antigen in the bronchial epithelium; bulky DNA adducts, 8-hydroxy-2-deoxyguanosine; multigene expression, and thiobarbituric acid-reactive aldehydes in whole lung and several other organs. Smoke-induced genomic and transcriptional alterations were suitable for evaluating their modulation by chemopreventive agent, as shown in studies using the thiol N-acetylcysteine and the nonsteroidal anti-inflammatory drug sulindac.

Strain-dependent differences in susceptibility to lung cancer in inbred mice exposed to mainstream cigarette smoke

“…In addition to A/J mice, increases in lung tumor multiplicity (tumors/animal) have been reported for BALB/C and SWR inbred mice [11], Swiss albino mice [13], and B6C3F1 [12] mice exposed to environmental or mainstream cigarette smoke. We did not observe a similar effect in SWR mice after exposure to mainstream cigarette smoke and there was only a modest increase, which did not reach statistical significance, in microscopic tumors/animals in BALB/C mice in our study.…”

“…Furthermore, based upon accumulating evidence in other murine models of cancer susceptibility, the low carcinogenic response to cigarette smoke observed in most mouse strains could very likely be the result of genetic insensitivity among the large variety of inbred mouse strains available to date. A systematic examination of murine interstrain differences in lung tumor response to cigarette smoke inhalation has not been conducted - only a few relevant inbred strains have been tested [11, 13, 14]. We have directly addressed this research gap by examining differences in lung tumor response among nine inbred strains of mice exposed to mainstream cigarette smoke using the exposure-recovery protocol of Witschi and colleagues [15].…”

Smoking and Smokeless Tobacco-Associated Human Buccal Cell Mutations and Their Association with Oral Cancer—A Review

“…Studies have documented a substantial increase in micronuclei in different animal species and for various tissues after exposure to tobacco smoke (reviewed in refs. 115,116). Notable is that in studies of lung macrophages and blood lymphocytes a significant increase in micronuclei frequencies was observed for exposed animals compared with nonexposed animals (refs.…”

Influence of FHIT on benzo[ a ]pyrene-induced tumors and alopecia in mice: Chemoprevention by budesonide and N -acetylcysteine

“…As expected, B[a]P induced a high multiplicity of lung tumors in all treated A͞J mice, whereas both incidence and multiplicity of lung tumors were modest in B6͞129 F 1 mice. Note that these mice are derived from C57BL͞6 mice, which are rather insensitive to the induction of lung tumors (32). In addition, B[a]P caused hyperplasia of the glandular stomach in an appreciable proportion of A͞J mice, whereas these histopathological alterations were infrequent in B6͞129 F 1 mice.…”