EGFL6 promotes bone metastasis of lung adenocarcinoma by increasing cancer cell malignancy and bone resorption

Lung adenocarcinoma is the most common and aggressive type of lung cancer with the highest incidence of bone metastasis. Epidermal growth factor-like domain multiple 6 (EGFL6) is an exocrine protein, and the expression of EGFL6 is correlated with survival of patient with lung adenocarcinoma. However, the association between EGFL6 expression in lung adenocarcinoma and bone metastasis has not been investigated. In this study, we found that EGFL6 levels in lung adenocarcinoma tissues correlate with bone metastasis and TNM stages in surgical patients. In vitro, overexpression of EGFL6 in lung adenocarcinoma cells promoted their proliferation, migration, and invasion ability compared with control by enhancing EMT process and activating Wnt/β-catenin and PI3K/AKT/mTOR pathways. In the nude mouse model, overexpression of EGFL6 enhanced tumor growth and caused greater bone destruction. Moreover, the exocrine EGFL6 of human lung adenocarcinoma cells increased osteoclast differentiation of bone marrow mononuclear macrophages (BMMs) of mice via the NF-κB and c-Fos/NFATc1 signaling pathways. However, exocrine EGFL6 had no effect on osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs). In conclusion, high expression of EGFL6 in lung adenocarcinomas is associated with bone metastasis in surgical patients. The underlying mechanism may be the increased metastatic properties of lung adenocarcinoma cells with high EGFL6 level and the enhanced osteoclast differentiation and bone resorption by exocrine EGFL6 from tumors. Therefore, EGFL6 is a potential therapeutic target to reduce the ability of lung adenocarcinomas to grow and metastasize and to preserve bone mass in patients with bone metastases from lung adenocarcinomas.