Abstract
CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in Kras(LA1) mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in Kras(LA1) mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in Kras(LA1) mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from Kras(LA1) mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from Kras(LA1) mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in Kras(LA1) mice. Treatment of Kras(LA1) mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS.
Highlights
Non–small cell lung cancer (NSCLC) is highly invasive and frequently metastatic at the time of diagnosis
We examined lung tissues from mice at an early stage of lung tumorigenesis (5 months old) when AAH and adenomas but no adenocarcinomas were present to identify chemokines that might play a role in tumorigenesis
We investigated biological evidence of these ligands in KrasLA1 mice by examining premalignant alveolar lesions for neutrophils and vascular endothelial cells, which are recruited by these CXCR2 ligands
Summary
Non–small cell lung cancer (NSCLC) is highly invasive and frequently metastatic at the time of diagnosis. RAS into cells is sufficient to confer transformed properties in vitro [19] In addition to these cellautonomous effects, Ras promotes tumorigenesis in vivo by eliciting a stromal response, an effect mediated, in part, through CXCR2 ligands [19], which we showed here to have relevance to lung cancer. We previously showed that Rac- and Akt-dependent pathways are activated in premalignant alveolar lesions of KrasLA1 mice [33, 34], and that these pathways cooperate to maintain the survival of lung cancer cells [35]. Oncogenic RAS induces cellular transformation through cellautonomous and stroma-dependent processes, both of which are activated through Rac- and Akt-dependent pathways, which cooperate to modulate the expression of a diverse set of downstream mediators
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