Role of the tumor microenvironment in the promotion of alveolar epithelial neoplasia induced by oncogenic KRAS.

CS08-02

Tumor-associated inflammation and neovascularization are prominent features of human lung adenocarcinomas, but the role of the tumor microenvironment in lung tumorigenesis has not been fully defined. Here we investigated the role of these process in Kras^LA1 mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We found inflammatory cells (neutrophils and macrophages) and endothelial cells in premalignant alveolar lesions, which increased in numbers with malignant progression of atypical alveolar hyperplasia (AAH) to adenocarcinoma in Kras^LA1 mice and in patients with lung adenocarcinoma. Macrophages highly expressed phosphorylated S6^Ser236/235, a downstream mediator of mTOR, and mTOR inhibition in K-ras^LA1 mice by treatment with CCI-779 decreased the size and number of AAH and adenomas and induced apoptosis of intra-epithelial macrophages. On the basis of these findings, we investigated the role of CXCL8, a ligand for the chemokine receptor CXCR2, which recruits inflammatory cells and endothelial cells to tumors and was recently reported to be a transcriptional target of oncogenic KRAS. CXCR2, KC, and MIP-2 were highly expressed in AAH and adenomas in Kras^LA1 mice and in the LKR-13 lung adenocarcinoma cell line derived from Kras^LA1 mice, and CXCR2 was required for the migration of murine endothelial cells, alveolar inflammatory cells, and LKR-13 cells in vitro. Treatment of Kras^LA1 mice with a CXCR2-neutralizing antibody blocked malignant progression and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with CCI-779 or the CXCR2-neutralizing antibody, LKR-13 cells established as syngeneic tumors recruited inflammatory cells and endothelial cells and were sensitive to either treatment, supporting a role for the tumor microenvironment as a target. Thus, tumor-associated inflammation promotes lung tumorigenesis induced by oncogenic KRAS, and strategies to target this process should be explored.