Abstract
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.
Highlights
Extracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating Extracellular Vesicles (EV) can provide diagnostic and prognostic information
The Western blot results showed that both MSCpos- and MSCneg-EVs were positive for conventional EV markers such as CD9, CD81 and Alix (Fig. 1C, left)
MSCpos‐EVs induce M2 polarization of macrophages through polymorphonuclear cells (PMN) released miR‐320 To clarify the potential role of EVs and their miRNA cargo in modulating the development of a protumorigenic microenvironment, we focused on investigating their effect on macrophages
Summary
Extracellular 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. Little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer. The 5-year relative survival rate of patients diagnosed with non-small-cell lung cancer (NSCLC), the most common lung cancer subtype Non invasive biomarkers able to assess cancer risk and improve early diagnosis [2] may impact on patients’ clinical management possibly reducing overall mortality. The Multicentric Italian Lung Detection (MILD) trial, provided additional evidence that extended intervention beyond 5 years, increased benefit (39% mortality reduction) of screening [4]. Blood samples are a suitable and obtainable source of biomarkers such as circulating cell-free tumor DNA, circulating microRNAs (miRNAs) and, more recently, extracellular vesicles (EVs)[6]
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