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G\u2010protein coupled receptor 64 (GPR64<\/jats:styled-content>), an orphan receptor with normal expression restricted to human epididymis is specifically over\u2010expressed in ES<\/jats:styled-content> among sarcoma, but also up\u2010regulated in a number of carcinomas derived from prostate, kidney or lung. Inhibition of GPR64<\/jats:styled-content> expression in ES<\/jats:styled-content> by RNA<\/jats:styled-content> interference impaired colony formation in vitro<\/jats:italic> and suppressed local tumour growth and metastasis in Rag2\u2212\/\u2212<\/jats:sup>\u03b3C<\/jats:sub>\u2212\/\u2212<\/jats:sup> mice. Microarray analysis after GPR64<\/jats:styled-content> knock down revealed a GPR64<\/jats:styled-content>\u2010mediated repression of genes involved in neuronal development like SLIT<\/jats:styled-content>, drosophila, homolog of, 2 (SLIT2<\/jats:styled-content>)<\/jats:italic>, and genes regulating transcription including pre\u2010B cell leukemia homeobox\u00a02 (PBX2<\/jats:styled-content>)<\/jats:italic>. Concurrently, the suppression of GPR64<\/jats:styled-content> increased ES<\/jats:styled-content> susceptibility to TRAIL<\/jats:styled-content> induced apoptosis. Moreover, a GPR64<\/jats:styled-content>\u2010mediated induction of placental growth factor (PGF<\/jats:styled-content>) in ES<\/jats:styled-content> was observed. PGF<\/jats:styled-content> suppression by RNA<\/jats:styled-content> interference resulted in a reduction of metastatic growth similar to that observed after GPR64<\/jats:styled-content> knock down. Importantly, inhibition of GPR64<\/jats:styled-content> as well as PGF<\/jats:styled-content> expression was associated with a reduced expression of matrix metalloproteinase (MMP<\/jats:styled-content>) 1 and invasiveness in vitro<\/jats:italic>. Furthermore, MMP1<\/jats:styled-content> knock down abrogated lung metastasis in Rag2\u2212\/\u2212<\/jats:sup>\u03b3C<\/jats:sub>\u2212\/\u2212<\/jats:sup> mice. Thus, GPR64<\/jats:styled-content> expression in ES<\/jats:styled-content> maintains an immature phenotype that is less sensitive to TRAIL<\/jats:styled-content>\u2010induced apoptosis and via its up\u2010regulation of PGF<\/jats:styled-content> and MMP1<\/jats:styled-content> orchestrates and promotes invasiveness and metastatic spread. Copyright \u00a9 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:bold><\/jats:p>","DOI":"10.1002\/path.4170","type":"journal-article","created":{"date-parts":[[2013,1,21]],"date-time":"2013-01-21T14:12:31Z","timestamp":1358777551000},"page":"70-81","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["G\u2010Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF<\/scp> and MMP1<\/scp>"],"prefix":"10.1002","volume":"230","author":[{"given":"G\u00fcnther HS","family":"Richter","sequence":"first","affiliation":[{"name":"Children's Cancer Research Center and Department of Paediatrics, Roman Herzog Comprehensive Cancer Research Center and Klinikum rechts der Isar Technische Universit\u00e4t M\u00fcnchen 81664 Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Fasan","sequence":"additional","affiliation":[{"name":"Children's Cancer Research Center and 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