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 transcriptional 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 (UL53-3×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 agents, as shown in studies using the thiol N-acetylcysteine and the nonsteroidal anti-inflammatory drug sulindac.

Key Words:

• chemoprevention
• cigarette smoke
• genomic alterations
• lung tumors
• murine models
• transcriptional alterations

Notes

The reported studies were supported by grants from the U.S. National Cancer Institute (Master Agreements N01-CN-75008 and N01-CN-05122), the Associazione Italiana per la Ricerca sul Cancro (AIRC), and the Bulgarian Ministry of Science and Education.