Key Points We established hypoxia-resistant cells that can mimic in vivo conditions of hypoxic bone marrow. Exosomal miR-135b derived from these cell lines enhanced endothelial tube formation under hypoxia via the HIF-FIH signaling pathway.

Recent findings indicate that specific microRNAs (miRNAs), such as those of the miR-17-92 cluster, may be responsible for regulating endothelial gene expression during tumor angiogenesis. Secreted miRNAs enclosed in exosomes also have an important role in cell-cell communication. To elucidate whether miRNAs secreted from neoplastic cells transfer into endothelial cells and are functionally active in the recipient cells, we investigated the effect of exosomal miRNAs derived from leukemia cells (K562) on human umbilical vein endothelial cells (HUVECs). As K562 cells released the miR-17-92 cluster, especially miR-92a, into the extracellular environment, K562 cells, transfected with Cy3-labeled pre-miR-92a, were co-cultured with HUVECs. Cy3-miR-92a derived from K562 cells was detected in the cytoplasm of HUVECs, and the Cy3-miR-92a co-localized with the signals of an exosomal marker, CD63. The expression of integrin α5, a target gene for miR-92a, was significantly reduced in HUVECs by exosomal miR-92a, indicating that exogenous miRNA via exosomal transport can function like endogenous miRNA in HUVECs. The most salient feature of this study is the exosome, derived from K562 cells with enforced miR-92a expression, did not affect the growth of HUVECs but did enhance endothelial cell migration and tube formation. Our results support the idea that exosomal miRNAs have an important role in neoplasia-to-endothelial cell communication.

Background:We recently showed communication between leukemia and endothelial cells and induction of angiogenesis via exosomes. Results: Hypoxic leukemia cells secrete exosomal miRNA, which enhances tube formation in endothelial cells. Conclusion: Exosomal miRNA from a tumor itself helps modulate the microenvironment of the tumor. Significance: This study provides novel insight into the role of exosomes in cancer development.

Key Points• Exosomal miR-340 derived from young BMSCs inhibited tumor angiogenesis via the HGF/c-MET signaling pathway.• The anti-angiogenic effect of exosomes from older BMSCs was restored by direct transfection of young BMSC-derived exosomal miRNAs.The study of bone marrow stromal cells (BMSCs) and the exosomes they secrete is considered promising for cancer therapy. However, little is known about the effect of donor age onBMSCs. In the present study, we investigated the therapeutic potential of BMSC exosomes derived from donors of different ages using an in vivo model of hypoxic bone marrow in multiple myeloma (MM). We found that donor age was strongly related to senescent changes

BackgroundWe undertook a study to evaluate the clinical relevance of miR-92a in plasma obtained from non-Hodgkin's lymphoma (NHL) patients, because the miR-17-92 polycistronic miRNA cluster plays a crucial role in lymphomagenesis and affects neo-angiogenesis.Methodology/Principal FindingsPlasma miR-92a values in NHL were extremely low (<5%), compared with healthy subjects (P<.0001), irrespective of lymphoma sub-type. The very low plasma level of miR-92a increased in the complete response (CR) phase but did not reach the normal range, and the plasma level was lower again in the relapse phase. Patients in CR or CR unconfirmed with a plasma miR-92a level of less than the cut-off level showed a significantly high relapse rate compared with patients with normalized plasma miR-92a level.Conclusions/SignificanceThe current results therefore indicate that the plasma miR-92a value could be a novel biomarker not only for diagnosis but also for monitoring lymphoma patients after chemotherapy.