Extracellular Vesicles in Lung Cancer: Bystanders or Main Characters?

Simple Summary Lung cancer is the biggest killer among cancers. Its mortality is related to delayed diagnosis which is often achieved in the advanced stages of the disease when surgery is no longer an option. Innovative treatments are now available for patients carrying specific genetic or immunological signatures. Tissue biopsy represents the gold standard sample to identify such life-changing therapeutic targets but obtaining it is not always easy, is often risky, and requires accurate radiological and clinical preliminary study. In this scenario, extracellular vesicles (EV), submicron particles released by both tumor and host cells, have been shown to carry strategical effectors and modulators of cancer development and to realize intercellular signaling. EV have been applied as a biosensor of disease showing high performance in both diagnosis and screening of lung cancer. As reviewed herein, circulating EV and especially those detected in body fluids in direct contact with lung cancer-bronchoalveolar lavage and pleural fluids-might convey not only tumor features but also key drivers of disease. Lung cancer still represents the main cause of cancer death worldwide. The poor survival is mainly related to the diagnosis which is often obtained in advanced stages when the disease is unresectable and characterized by the worst prognosis. Only in the last decades have great discoveries led to the development of new therapies targeted to oncogenes and to boost the host immune response against the tumor. Tumor identification and molecular/immunological characterization rely on bioptic samples which represent the gold standard for diagnosis. Nonetheless, less invasive procedures providing small samples will be more and more common in the future. Extracellular vesicles (EV), submicron particles released by any cell type, are candidates for diagnostic and prognostic biomarkers. EV are mediators of intercellular communication and can convey cytokines, miRNAs, antigens, and many other factors of tumorigenesis. This review summarizes the most appealing findings on lung-cancer-related EV, debating the evidence on circulating versus airway EV as potential biomarkers in disease management and the main studies on the role of these particles on lung cancer pathogenesis. Overall, the available results point toward a wide range of possible applications, supported by the promising achievements of genotyping on BAL fluid EV and proteomic analysis on pleural effusion EV. Nonetheless, the study of lung EV is still affected by remarkable methodological issues, especially when in vitro evidence is translated into humans. Whether EV still represent an "information fog" or can be useful in lung cancer management will be discussed, with possible hints on how to improve their usage.