The A/J mouse is highly susceptible to lung
tumor induction and has been widely used as a screening model in carcinogenicity testing and
chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung
tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical
carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette
smoke-related lung
tumors in the A/J mouse model using
mRNA and
microRNA (
miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette
smoke (MS) for 18 months. Gene expression interaction term analysis of lung
tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m(3) MS or
sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis(®) (IPA(®)) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of
sphingolipid and
glycosaminoglycan metabolism and a deregulation of potentially oncogenic
miRNA in
tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for
tumor recognition by the immune system, thereby potentiating the ability of
tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of
miRNA, which have previously been implicated in
carcinogenesis and are thought to contribute to
tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette
smoke-related and spontaneous lung
tumors.