title: K-ras activation generates an inflammatory response in lung tumors.
abstract: Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras(G12D) alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.forename: A M
authors.initials: AM
authors.lastname: Houghton
authors.forename: T J
authors.initials: TJ
authors.lastname: Mariani
authors.forename: S
authors.initials: S
authors.lastname: Perera
authors.forename: C B
authors.initials: CB
authors.lastname: Kim
authors.forename: R
authors.initials: R
authors.lastname: Padera
authors.forename: G
authors.initials: G
authors.lastname: Tonon
authors.forename: K
authors.initials: K
authors.lastname: McNamara
authors.forename: L A
authors.initials: LA
authors.lastname: Marconcini
authors.forename: A
authors.initials: A
authors.lastname: Hezel
authors.forename: N
authors.initials: N
authors.lastname: El-Bardeesy
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: D
authors.initials: D
authors.lastname: Sugarbaker
authors.forename: R S
authors.initials: RS
authors.lastname: Maser
authors.forename: S D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: K-K
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid; D045744:Cell Line, Tumor; D017931:DNA Primers; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D011014:Pneumonia / Q000150:complications / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers