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K-ras activation generates an inflammatory response in lung tumors
H Ji1, A M Houghton, T J Mariani
1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Oncogene
|November 17, 2005
Summary
Activating K-ras mutations in lung epithelial cells drive lung adenocarcinoma and trigger a significant inflammatory response. This mouse model reveals K-ras-induced chemokines that attract immune cells, impacting tumor progression and survival.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Activating mutations in K-ras are frequent in human lung cancer.
- Understanding K-ras activation's role in lung tumorigenesis is crucial.
Purpose of the Study:
- To create a mouse model dissecting K-ras activation's role in bronchial epithelial cells during lung adenocarcinoma development.
- To investigate the inflammatory response associated with K-ras activation in the lung.
Main Methods:
- Generated a conditional mutant mouse model with CC10-Cre recombinase and Lox-Stop-Lox K-ras(G12D) alleles.
- Observed tumor progression from cellular atypia to adenocarcinoma.
- Analyzed bronchoalveolar lavage fluid and derived cell lines for chemokine expression.
Main Results:
- K-ras activation in CC10-positive cells led to progressive lung adenocarcinoma.
- A robust inflammatory response with macrophage and neutrophil infiltration was observed.
- Elevated levels of MIP-2, KC, MCP-1, and LIX chemokines were detected in mutant mice, with tumor-derived cell lines producing these chemokines.
Conclusions:
- K-ras activation in lung epithelial cells induces inflammatory chemokines, promoting tumor progression.
- This model provides a platform for studying the interplay between inflammation, chemokines, and lung tumorigenesis.
- Early mortality in the model is linked to the pulmonary inflammatory response.
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