Abstract
Abstract Metastatic spread in Ewing Tumors (ET) is frequent and hematogenous. Microarray analysis revealed the G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis, to be over-expressed in ET. Members of this family of receptors have been implicated with vascularization and neuronal development. Inhibition of GPR64 expression by RNA interference impaired endothelial differentiation in vitro and suppressed local tumor growth and metastasis in Rag2-/-γC-/- mice. Microarray analysis of ET after GPR64 knock down revealed a GPR64-mediated suppression of genes involved in differentiation like v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), and genes stimulating transcriptional activation including pre-B cell leukemia homeobox 2 (PBX2) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4). Similarly, a GPR64-mediated induction of VEGF receptor 1 ligand placental growth factor (PGF) in ET was observed. PGF itself was induced by EWS-FLI1 in mesenchymal stem cells. The GPR64-mediated induction of placental growth factor (PGF) and repression of PGF resulted in a phenotype similar observed after GPR64 knockdown. GPR64 as well as PGF inhibition was associated with reduced proteolytic activity of Matrix Metalloproteinase (MMP) 1 and invasiveness in vitro. MMP1 knock down abrogated lung metastasis in Rag2-/-γC-/- mice. GPR64 and subsequent up-regulation of PGF and MMP1 orchestrate and promote invasiveness and metastatic spread of this tumor, and provide significant conceptual progress in understanding both the histogenesis of ET in particular and the pathogenesis of metastatic dispersal in general. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2427. doi:10.1158/1538-7445.AM2011-2427
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