Tumor-Derived Exosomes Induce the Formation of Neutrophil Extracellular Traps: Implications For The Establishment of Cancer-Associated Thrombosis.

Cancer patients are at an increased risk of developing thromboembolic complications. Several mechanisms have been proposed to explain cancer-associated thrombosis including the release of tumor-derived extracellular vesicles and the activation of host vascular cells. It was proposed that neutrophil extracellular traps (NETs) contribute to the prothrombotic phenotype in cancer. In this study, we evaluated the possible cooperation between tumor-derived exosomes and NETs in cancer-associated thrombosis. Female BALB/c mice were orthotopically injected with 4T1 breast cancer cells. The tumor-bearing animals exhibited increased levels of plasma DNA and myeloperoxidase in addition to significantly increased numbers of circulating neutrophils. Mice were subjected to either Rose Bengal/laser-induced venous thrombosis or ferric chloride-induced arterial thrombosis models. The tumor-bearing mice exhibited accelerated thrombus formation in both models compared to tumor-free animals. Treatment with recombinant human DNase 1 reversed the prothrombotic phenotype of tumor-bearing mice in both models. Remarkably, 4T1-derived exosomes induced NET formation in neutrophils from mice treated with granulocyte colony-stimulating factor (G-CSF). In addition, tumor-derived exosomes interacted with NETs under static conditions. Accordingly, the intravenous administration of 4T1-derived exosomes into G-CSF-treated mice significantly accelerated venous thrombosis in vivo. Taken together, our observations suggest that tumor-derived exosomes and neutrophils may act cooperatively in the establishment of cancer-associated thrombosis.

Tumor-cell-derived microvesicles as carriers of molecular information in cancer.

PURPOSE OF REVIEW: Exosomes and microvesicles are secreted particles of 30-200  nm in diameter, delimited by a lipid bilayer and containing a wide range of membrane-bound or free proteins and nucleic acids (in particular mRNA and miRNA). Here, we review the properties of tumor-cell-derived microvesicles as carriers of molecular information in relation to cancer progression and promotion of metastasis. RECENT FINDINGS: Microvesicles from tumor cells operate as signaling platforms that diffuse in the extracellular space to target cells in the microenvironment, modulating the interactions of tumor cells with stromal, inflammatory, dendritic, immune or vascular cells and priming the formation of the metastatic niche. SUMMARY: Because of their stability, exosomes and microvesicles can be retrieved in bodily fluids as biomarkers for cancer detection and monitoring. They offer a range of molecular targets for controlling cell-cell interactions during invasion and metastasis.