title: Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model.
abstract: 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.
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland ; Both authors contributed equally to this manuscript.
authors.forename: Karsta
authors.initials: K
authors.lastname: Luettich
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland ; Both authors contributed equally to this manuscript.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Iskandar
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: Sewer
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Martin
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland ; Philip Morris Research Laboratories bvba, 3001 Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanscheeuwijck
authors.affiliation: Philip Morris Research Laboratories bvba, 3001 Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Berges
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Emilija
authors.initials: E
authors.lastname: Veljkovic
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Schlage
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
authors.affiliation: Biological Systems Research, Philip Morris International Research and Development, CH-2000 Neuchâtel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Peitsch
keywords: A/J mouse; cigarette smoke exposure; gene expression; lung tumorigenesis; microRNA (miRNA) expression