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Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.<\/jats:p>\n                  <jats:p>Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)\u2013educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.<\/jats:p>\n                  <jats:p>Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGF\u03b2, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGF\u03b2-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGF\u03b2 are increased in osteosarcoma patients.<\/jats:p>\n                  <jats:p>Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGF\u03b2-blocking agents as new therapeutic options for osteosarcoma patients. Clin Cancer Res; 23(14); 3721\u201333. \u00a92017 AACR.<\/jats:p>","DOI":"10.1158\/1078-0432.ccr-16-2726","type":"journal-article","created":{"date-parts":[[2017,1,4]],"date-time":"2017-01-04T21:40:20Z","timestamp":1483566020000},"page":"3721-3733","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":166,"title":["Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression"],"prefix":"10.1158","volume":"23","author":[{"given":"S. Rubina","family":"Baglio","sequence":"first","affiliation":[{"name":"1Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Tonny","family":"Lagerweij","sequence":"additional","affiliation":[{"name":"2Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Maria","family":"P\u00e9rez-Lanz\u00f3n","sequence":"additional","affiliation":[{"name":"1Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Xuan Dung","family":"Ho","sequence":"additional","affiliation":[{"name":"3Department of Pathophysiology, University of Tartu, Tartu, Estonia."},{"name":"4Department of Traumatology and Orthopedics, University of Tartu, Tartu, Estonia."},{"name":"5Department of Oncology, Hue College of Medicine and Pharmacy, Hue University, Hue, Vietnam."}]},{"given":"Nicolas","family":"L\u00e9veill\u00e9","sequence":"additional","affiliation":[{"name":"6Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), Amsterdam, the Netherlands."}]},{"given":"Sonia A.","family":"Melo","sequence":"additional","affiliation":[{"name":"7Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto (i3S) and Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200 Porto, Portugal."}]},{"given":"Anne-Marie","family":"Cleton-Jansen","sequence":"additional","affiliation":[{"name":"8Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands."}]},{"given":"Ekaterina S.","family":"Jordanova","sequence":"additional","affiliation":[{"name":"9Department of Obstetrics and Gynecology, Center for Gynecological Oncology Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Laura","family":"Roncuzzi","sequence":"additional","affiliation":[{"name":"10Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy."}]},{"given":"Michelina","family":"Greco","sequence":"additional","affiliation":[{"name":"10Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy."}]},{"given":"Monique A.J.","family":"van Eijndhoven","sequence":"additional","affiliation":[{"name":"1Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Giulia","family":"Grisendi","sequence":"additional","affiliation":[{"name":"11Division of Oncology, Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy."}]},{"given":"Massimo","family":"Dominici","sequence":"additional","affiliation":[{"name":"11Division of Oncology, Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy."}]},{"given":"Roberta","family":"Bonafede","sequence":"additional","affiliation":[{"name":"1Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."},{"name":"12Department of Neurosciences, Biomedicine and Movement Sciences. University of Verona, Verona, Italy."}]},{"given":"Sinead M.","family":"Lougheed","sequence":"additional","affiliation":[{"name":"13Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Tanja D.","family":"de Gruijl","sequence":"additional","affiliation":[{"name":"13Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."}]},{"given":"Nicoletta","family":"Zini","sequence":"additional","affiliation":[{"name":"14CNR\u2014National Research Council of Italy, Institute of Molecular Genetics, Bologna, Italy."},{"name":"15Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopaedic Institute, Bologna, Italy."}]},{"given":"Silvia","family":"Cervo","sequence":"additional","affiliation":[{"name":"16CRO-Biobank, CRO Aviano National Cancer Institute, Aviano, Italy."},{"name":"17Clinical Cancer Pathology, CRO Aviano National Cancer Institute, Aviano, Italy."}]},{"given":"Agostino","family":"Steffan","sequence":"additional","affiliation":[{"name":"16CRO-Biobank, CRO Aviano National Cancer Institute, Aviano, Italy."},{"name":"17Clinical Cancer Pathology, CRO Aviano National Cancer Institute, Aviano, Italy."}]},{"given":"Vincenzo","family":"Canzonieri","sequence":"additional","affiliation":[{"name":"16CRO-Biobank, CRO Aviano National Cancer Institute, Aviano, Italy."},{"name":"18Division of Pathology, CRO Aviano National Cancer Institute, Aviano, Italy."}]},{"given":"Aare","family":"Martson","sequence":"additional","affiliation":[{"name":"4Department of Traumatology and Orthopedics, University of Tartu, Tartu, Estonia."},{"name":"19Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Tartu, Estonia."}]},{"given":"Katre","family":"Maasalu","sequence":"additional","affiliation":[{"name":"4Department of Traumatology and Orthopedics, University of Tartu, Tartu, Estonia."},{"name":"19Clinic of Traumatology and Orthopaedics, Tartu University Hospital, Tartu, Estonia."}]},{"given":"Sulev","family":"K\u00f6ks","sequence":"additional","affiliation":[{"name":"3Department of Pathophysiology, University of Tartu, Tartu, Estonia."},{"name":"20Department of Reproductive Biology, Estonian University of Life Sciences, Tartu, Estonia."}]},{"given":"Tom","family":"Wurdinger","sequence":"additional","affiliation":[{"name":"2Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands."},{"name":"21Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts."}]},{"given":"Nicola","family":"Baldini","sequence":"additional","affiliation":[{"name":"10Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy."},{"name":"22Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy."}]},{"given":"D. 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