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      Tumour exosome integrins determine organotropic metastasis

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      1 , 1 , 1 , 2 , 1 , 3 , 1 , 4 , 5 , 5 , 6 , 1 , 7 , 1 , 1 , 8 , 8 , 9 , 9 , 1 , 10 , 11 , 1 , 12 , 1 , 1 , 13 , 1 , 14 , 14 , 14 , 15 , 16 , 17 , 10 , 18 , 19 , 20 , 20 , 1 , 3 , 21 , 21 , 21 , 21 , 13 , 1 , 22 , 23 , 24 , 25 , 26 , 27 , 11 , 28 , 29 , 30 , 31 , 32 , 1 , 1 , 33 , 34 , 35 , 1 , 14
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          Abstract

          Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6β 4 and α 6β 1 were associated with lung metastasis, while exosomal integrin α vβ 5 was linked to liver metastasis. Targeting the integrins α 6β 4 and α vβ 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

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          Genes that mediate breast cancer metastasis to the brain.

          The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.
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            The distribution of secondary growths in cancer of the breast. 1889.

            S. PAGET (1989)
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              Proteomics, transcriptomics and lipidomics of exosomes and ectosomes.

              Mammalian cells secrete two types of extracellular vesicles either constitutively or in a regulated manner: exosomes (50-100 nm in diameter) released from the intracellular compartment and ectosomes (also called microvesicles, 100-1000 nm in diameter) shed directly from the plasma membrane. Extracellular vesicles are bilayered proteolipids enriched with proteins, mRNAs, microRNAs, and lipids. In recent years, much data have been collected regarding the specific components of extracellular vesicles from various cell types and body fluids using proteomic, transcriptomic, and lipidomic methods. These studies have revealed that extracellular vesicles harbor specific types of proteins, mRNAs, miRNAs, and lipids rather than random cellular components. These results provide valuable information on the molecular mechanisms involved in vesicular cargo-sorting and biogenesis. Furthermore, studies of these complex extracellular organelles have facilitated conceptual advancements in the field of intercellular communication under physiological and pathological conditions as well as for disease-specific biomarker discovery. This review focuses on the proteomic, transcriptomic, and lipidomic profiles of extracellular vesicles, and will briefly summarize recent advances in the biology, function, and diagnostic potential of vesicle-specific components. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                31 October 2015
                28 October 2015
                19 November 2015
                18 May 2016
                : 527
                : 7578
                : 329-335
                Affiliations
                [1 ]Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA
                [2 ]Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan
                [3 ]Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal
                [4 ]Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
                [5 ]Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA
                [6 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [7 ]Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
                [8 ]Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA
                [9 ]Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA
                [10 ]Department of Surgery, County Council of Östergötland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 58185 Linköping, Sweden
                [11 ]Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
                [12 ]Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA
                [13 ]Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [14 ]Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [15 ]Division of Pediatric Oncology, Alberta Children’s Hospital, Calgary, Alberta T3B 6A8, Canada
                [16 ]Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA
                [17 ]Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [18 ]Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway
                [19 ]Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway
                [20 ]Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
                [21 ]Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
                [22 ]Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [23 ]Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway
                [24 ]Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway
                [25 ]Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany
                [26 ]Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
                [27 ]Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                [28 ]Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
                [29 ]Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
                [30 ]Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
                [31 ]Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [32 ]Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
                [33 ]Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain
                [34 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
                [35 ]Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA
                Author notes
                Correspondence and requests for materials should be addressed to H.P. ( hpeinado@ 123456cnio.es ), J.B. ( bromberj@ 123456mskcc.org ) or D.L. ( dcl2001@ 123456med.cornell.edu )
                [*]

                These authors contributed equally to this work.

                Article
                NIHMS727229
                10.1038/nature15756
                4788391
                26524530
                12498d29-871a-433f-984d-0881c36c8bde

                Reprints and permissions information is available at www.nature.com/reprints

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