Upregulation of cytoskeleton protein and extracellular matrix protein induced by stromal-derived nitric oxide promotes lung cancer invasion and metastasis.

Lung cancer commonly metastasizes to lymph nodes, brain and bones, which is the main cause of death. It is still a challenge to detect molecular biomarkers for early diagnosis and therapeutics of lung cancer. Our previous study found that bone marrow-derived stroma cells (BMSCs) under tumor microenvironment produced nitric oxide (NO), which was induced by inducible nitric oxide synthase (iNOS), and promoted invasion and metastasis of cancer cells by remodeling cytoskeleton. The aim of this study is to elucidate the relationship between the expressions of iNOS, cytoskeleton protein caldesmon, OPN, and clinical parameters especially the metastasis of lung cancer. We found that nitric oxide can remodel cytoskeleton and promoted the mobility of lung cancer cells. The expressions of iNOS, caldesmon, and OPN are closely correlated to metastasis of lung cancer. The intracranial metastatic tissue samples of lung cancer showed significantly higher expression of iNOS, caldesmon and OPN. A flow-cytometry analysis for peripheral blood of lung cancer patients showed increased EPCAM+/OPN+ cells in circulation of patients with bone metastasis compared to that of patients without metastasis, which is indicative of cancer circulating cells. The concentration of serum OPN was also positively related to the bone metastasis of lung cancer. Taken together, these results suggested that iNOS, caldesmon and OPN may work as biomarkers for metastasis of lung cancer.