K-ras activation generates an inflammatory response in lung tumors.
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.
Ji
H
H
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Houghton
A M
AM
Mariani
T J
TJ
Perera
S
S
Kim
C B
CB
Padera
R
R
Tonon
G
G
McNamara
K
K
Marconcini
L A
LA
Hezel
A
A
El-Bardeesy
N
N
Bronson
R T
RT
Sugarbaker
D
D
Maser
R S
RS
Shapiro
S D
SD
Wong
K-K
KK
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
D017931:DNA Primers