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      Potential Roles of Tumor-derived Exosomes in Angiogenesis

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          Abstract

          Introduction:

          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.

          Areas covered:

          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.

          Expert opinion:

          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.

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          Most cited references37

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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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            Tumor-Derived Exosomes and Their Role in Cancer Progression.

            Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation.
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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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                Author and article information

                Journal
                101127833
                27020
                Expert Opin Ther Targets
                Expert Opin. Ther. Targets
                Expert opinion on therapeutic targets
                1472-8222
                1744-7631
                3 August 2018
                26 April 2018
                May 2018
                01 May 2019
                : 22
                : 5
                : 409-417
                Affiliations
                [1 ]Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
                [2 ]Departments of Immunology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
                [3 ]UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
                Author notes

                First author: Nils Ludwigm, UPMC Hillman Cancer Center, UPCI Research Pavilion, Suite 1.27, 5117 Centre Avenue, Pittsburgh, PA 15213, Phone: +1(412) 551-9025, ludwign@ 123456upmc.edu

                Corresponding author: Theresa L. Whiteside, UPMC Hillman Cancer Center, UPCI Research Pavilion, Suite 1.27, 5117 Centre Avenue, Pittsburgh, PA 15213, Phone: (412) 624-0096, Fax: (412) 624-0264, whitesidetl@ 123456upmc.edu
                Article
                PMC6126896 PMC6126896 6126896 nihpa1501010
                10.1080/14728222.2018.1464141
                6126896
                29634426
                6242def0-c15b-4d74-9fae-1960967fd9e1
                History
                Categories
                Article

                angiogenesis,endothelial cells,tumor-derived exosomes (TEX),hypoxia

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