RESUMO
Exosomes represent extracellular vesicles of endocytic origin ranging from 30 to 100 nm that are released by most of eukaryotic cells and can be found in body fluids. These vesicles in carrying DNA, RNA, microRNA (miRNA), Long noncoding RNA, proteins, and lipids serve as intercellular communicators. Due to their role in crosstalk between tumor cells and mesenchymal stroma cells, they are vital for tumor growth, progression, and anticancer drug resistance. Lung cancer is a global leading cause of cancer-related deaths with 5-year survival rates of about 7% in patients with distant metastasis. Although the implementation of targeted therapy has improved the clinical outcome of nonsmall cell lung cancer, drug resistance remains a major obstacle. Lung tumor-derived exosomes (TDEs) conveying molecular information from tumor cells to their neighbor cells or cells at distant sites of the body activate the tumor microenvironment (TME) and facilitate tumor metastasis. Exosomal miRNAs are also considered as noninvasive biomarkers for early diagnosis of lung cancer. This review summarizes the influence of lung TDEs on the TME and metastasis. Their involvement in targeted therapy resistance and potential clinical applications are discussed. Additionally, challenges encountered in the development of exosome-based therapeutic strategies are addressed.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Exossomos , Neoplasias Pulmonares , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Exossomos/metabolismo , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Microambiente TumoralRESUMO
Fibulins (FBLNs), interacting with cell adhesion receptors and extracellular matrix (ECM) components, play multiple roles in ECM structures and tissue functions. Abnormal expression of FBLN2, one of the fibulin family members, contributes to tumor initiation and development. However, the function of FBLN2 in human non-small cell lung cancer (NSCLC) has not yet been elucidated. In this study, we found that FBLN2 was downregulated in 9 out of 11 lung cancer cell lines compared to normal bronchial epithelial cells, which was associated with DNA hypermethylation. Primary lung squamous cell carcinoma expressed significantly more FBLN2 protein compared to adenocarcinoma (p = 0.047). Ectopic expression of FBLN2 led to decreased cell proliferation, migration and invasion, accompanied by inactivated MAPK/ERK and AKT/mTOR pathways, while FBLN2 siRNA knockdown resulted in an opposite biological behaviour in NSCLC cells. Additionally, overexpression of FBLN2 led to dysregulation of cell adhesion molecules, ECM markers and a panel of lysate/exosome-derived-microRNAs, which are involved in cell adhesion and ECM remodelling. Taken together, our data indicate that FBLN2 is methylated and exerts a tumor suppressor function through modulation of MAPK/ERK and AKT pathways and regulation of cell adhesion and ECM genes. Moreover, FBLN2 might be a potential biomarker for the sub-classification of NSCLC.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Supressoras de Tumor/metabolismo , Células A549 , Proteínas de Ligação ao Cálcio/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Adesão Celular , Matriz Extracelular/genética , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Supressoras de Tumor/genéticaRESUMO
Epithelial membrane proteins (EMP1-3) are involved in epithelial differentiation and carcinogenesis. Dysregulated expression of EMP2 was observed in various cancers, but its role in human lung cancer is not yet clarified. In this study, we analyzed the expression of EMP1-3 and investigated the biological function of EMP2 in non-small cell lung cancer (NSCLC). The results showed that lower expression of EMP1 was significantly correlated with tumor size in primary lung tumors (p = 0.004). Overexpression of EMP2 suppressed tumor cell growth, migration, and invasion, resulting in a G1 cell cycle arrest, with knockdown of EMP2 leading to enhanced cell migration, related to MAPK pathway alterations and disruption of cell cycle regulatory genes. Exosomes isolated from transfected cells were taken up by tumor cells, carrying EMP2-downregulated microRNAs (miRNAs) which participated in regulation of the tumor microenvironment. Our data suggest that decreased EMP1 expression is significantly related to increased tumor size in NSCLC. EMP2 suppresses NSCLC cell growth mainly by inhibiting the MAPK pathway. EMP2 might further affect the tumor microenvironment by regulating tumor microenvironment-associated miRNAs.