Abstract
Malignant pleural effusion (MPE) is a common clinical problem in non-small cell lung carcinoma (NSCLC) patients; however, the underlying mechanisms are still largely unknown. Recent studies indicate that the frequency of the L858R mutant form of the epidermal growth factor receptor (EGFR-L858R) is higher in lung adenocarcinoma with MPE than in surgically resected specimens, suggesting that lung adenocarcinoma cells harboring this mutation tend to invade the adjacent pleural cavity. The purpose of this study was to clarify the relationship between the EGFR-L858R mutation and cancer cell invasion ability and to investigate the molecular mechanisms involved in the formation of MPE. We found that expression of EGFR-L858R in lung cancer cells resulted in up-regulation of the CXCR4 in association with increased cancer cell invasive ability and MPE formation. Ectopic expression of EGFR-L858R in lung cancer cells acted through activation of ERK signaling pathways to induce the expression of CXCR4. We also indicated that Inhibition of CXCR4 with small interfering RNA, neutralizing antibody, or receptor antagonist significantly suppressed the EGFR-L858R–dependent cell invasion. These results suggest that targeting the production of CXCR4 and blocking the CXCL12-CXCR4 pathway might be effective strategies for treating NSCLCs harboring a specific type of EGFR mutation.
Highlights
Have malignant pleural effusion (MPE) at the time of initial diagnosis, and 50% develop it later in the course of their disease[3,4]
We show that the EGFR-L858R mutant increases lung adenocarcinoma cell invasion ability and promotes formation of MPE
We further found that this increase in CXCR4 expression was central to the effects of EGFR-L858R, showing that small interfering RNA (siRNA)-mediated knockdown of CXCR4 or inhibition of CXCR4 with a neutralizing antibody or antagonist significantly suppressed the invasion ability of H1299-EGFR-L858R cells
Summary
Have MPE at the time of initial diagnosis, and 50% develop it later in the course of their disease[3,4]. Patients with stage IV lung adenocarcinoma with MPE at initial diagnosis have a shorter overall survival and higher rate of EGFR mutations, especially L858R, than patients who develop MPE following disease progression[14]. From these observations, it has been postulated that mutation of the EGFR is an early event in the pathogenesis of lung adenocarcinoma. Our findings demonstrate that lung adenocarcinomas harboring the EGFR-L858R mutation exhibit increased cancer cell invasive ability and MPE formation through activation of the CXCL12-CXCR4 axis
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