Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320

Journal of Experimental & Clinical Cancer Research

Anna Maria Ferretti¹  Paola Suatoni²  Ugo Pastorino²  Mavis Mensah³  Giovanni Centonze³  Luca Roz³  Miriam Segale³  Giulia Bertolini³  Gabriella Sozzi³  Ilaria Petraroia³  Orazio Fortunato³  Francesca Pontis³  Massimo Moro³ 

[1] Istituto Di Scienze E Tecnologie Chimiche-CNR, Via G. Fantoli 16/15, 20138, Milan, Italy;Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, 20133, Milan, Italy;Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Venezian 1, 20133, Milan, Italy;

关键词: Extracellular vesicles;    microRNA;    Lung cancer;   

DOI  :  10.1186/s13046-021-02040-3

来源: Springer

【 摘 要 】

BackgroundExtracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating EVs can provide diagnostic and prognostic information. To date, little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer.MethodsPlasma EVs were isolated from 40 cancer-free heavy-smokers classified according to a validated 24-microRNA signature classifier (MSC) at high (MSCpos-EVs) or low (MSCneg-EVs) risk to develop lung cancer. EVs origin and functional properties were investigated using in vitro 3D cultures and in vivo models. The prognostic value of miRNAs inside EVs was assessed in training and in validation cohorts of 54 and 48 lung cancer patients, respectively.ResultsDifferent membrane composition, biological cargo and pro-tumorigenic activity were observed in MSCpos vs MSCneg-EVs. Mechanistically, in vitro and in vivo results showed that miR-126 and miR-320 from MSCpos-EVs increased pro-angiogenic phenotype of endothelial cells and M2 polarization of macrophage, respectively. MSCpos-EVs prompted 3D proliferation of non-tumorigenic epithelial cells through c-Myc transfer. Moreover, hypoxia was shown to stimulate the secretion of EVs containing c-Myc from fibroblasts, miR-126-EVs from endothelial cells and miR-320-EVs from granulocytes. Lung cancer patients with higher levels of mir-320 into EVs displayed a significantly shorter overall survival in training [HR2.96] and validation sets [HR2.68].ConclusionOverall our data provide a new perspective on the pro-tumorigenic role of circulating EVs in high risk smokers and highlight the significance of miR-320-EVs as a new prognostic biomarker in lung cancer patients.

【 授权许可】

CC BY