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      Potential roles of tumor-derived exosomes in angiogenesis

      1 , 2 , 1 , 3 , 2

      Expert Opinion on Therapeutic Targets

      Informa UK Limited

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d3619914e137">Introduction:</h5> <p id="P2">Tumor-derived exosomes (TEX) and their role in tumor progression by accelerating angiogenesis are of great current interest. A better understanding of the mechanisms underlying TEX-blood vessels cross-talk may lead to improvements in current diagnosis, prognosis and treatment of cancer. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d3619914e142">Areas covered:</h5> <p id="P3">For solid tumors, an adequate blood supply is of critical importance for their development, growth and metastasis. TEX, virus-size vesicles which circulate freely throughout body fluids and accumulate in the tumor microenvironment (TME), have been recognized as a new contributor to angiogenesis. TEX serve as a communication system between the tumor and various normal cells and are responsible for functional reprogramming of these cells. The molecular and genetic cargos that TEX deliver to the recipient cells involved in angiogenesis promote its induction and progression. The targeted inhibition of TEX pro-angiogenic functions might be a novel therapeutic approach for control of tumor progression. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d3619914e147">Expert opinion:</h5> <p id="P4">TEX circulating in body fluids of cancer patients carry a complex molecular and genetic cargo and are responsible for phenotypic and functional reprogramming of endothelial cells and other normal cells residing in the TME. </p> </div>

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          Most cited references 37

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          Cellular internalization of exosomes occurs through phagocytosis.

          Exosomes play important roles in many physiological and pathological processes. However, the exosome-cell interaction mode and the intracellular trafficking pathway of exosomes in their recipient cells remain unclear. Here, we report that exosomes derived from K562 or MT4 cells are internalized more efficiently by phagocytes than by non-phagocytic cells. Most exosomes were observed attached to the plasma membrane of non-phagocytic cells, while in phagocytic cells these exosomes were found to enter via phagocytosis. Specifically, they moved to phagosomes together with phagocytic polystyrene carboxylate-modified latex beads (biospheres) and were further sorted into phagolysosomes. Moreover, exosome internalization was dependent on the actin cytoskeleton and phosphatidylinositol 3-kinase, and could be inhibited by the knockdown of dynamin2 or overexpression of a dominant-negative form of dynamin2. Further, antibody pretreatment assays demonstrated that tim4 but not tim1 was involved in exosomes uptake. We also found that exosomes did not enter the internalization pathway involving caveolae, macropinocytosis and clathrin-coated vesicles. Our observation that the cellular uptake of exosomes occurs through phagocytosis has important implications for exosome-cell interactions and the exosome intracellular trafficking pathway.
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            Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes.

            Under hypoxia, tumor cells produce a secretion that modulates their microenvironment to facilitate tumor angiogenesis and metastasis. Here, we observed that hypoxic or reoxygenated A431 carcinoma cells exhibited enhanced angiogenic and metastatic potential such as reduced cell-cell and cell-extracellular matrix adhesion, increased invasiveness, and production of a secretion with increased chorioallantoic membrane angiogenic activity. Consistent with these observations, quantitative proteomics revealed that under hypoxia the tumor cells secreted proteins involved in angiogenesis, focal adhesion, extracellular matrix-receptor interaction, and immune cell recruitment. Unexpectedly, the secreted proteins were predominantly cytoplasmic and membrane proteins. Ultracentrifugation at 100,000 x g precipitated 54% of the secreted proteins and enriched for many exosome-associated proteins such as the tetraspanins and Alix and also proteins with the potential to facilitate angiogenesis and metastasis. Two tetraspanins, CD9 and CD81, co-immunoprecipitated. Together, these data suggested that tumor cells secrete proteins and exosomes with the potential to modulate their microenvironment and facilitate angiogenesis and metastasis.
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              Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo.

              Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Journal
                Expert Opinion on Therapeutic Targets
                Expert Opinion on Therapeutic Targets
                Informa UK Limited
                1472-8222
                1744-7631
                April 20 2018
                May 04 2018
                April 26 2018
                May 04 2018
                : 22
                : 5
                : 409-417
                Affiliations
                [1 ] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
                [2 ] UPMC Hillman Cancer Center, Pittsburgh, PA, USA
                [3 ] Departments of Immunology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
                Article
                10.1080/14728222.2018.1464141
                6126896
                29634426
                © 2018

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