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Richter, G.H.S.* ; Fasan, A.* ; Hauer, K.* ; Grunewald, T.G.P.* ; Berns, C.* ; Rössler, S.* ; Naumann, I.* ; Staege, M.S.* ; Fulda, S.* ; Esposito, I. ; Burdach, S.*

G-protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1.

J. Pathol. 230, 70-81 (2013)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Metastatic spread in Ewing sarcomas (ES) is frequent and haematogenous. G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis is specifically over-expressed in ES among sarcoma, but also up-regulated in a number of carcinomas derived from prostate, kidney or lung. Inhibition of GPR64 expression in ES by RNA interference impaired colony formation in vitro and suppressed local tumour growth and metastasis in Rag2/C/ mice. Microarray analysis after GPR64 knock down revealed a GPR64-mediated repression of genes involved in neuronal development like SLIT, drosophila, homolog of, 2 (SLIT2), and genes regulating transcription including pre-B cell leukemia homeobox2 (PBX2). Concurrently, the suppression of GPR64 increased ES susceptibility to TRAIL induced apoptosis. Moreover, a GPR64-mediated induction of placental growth factor (PGF) in ES was observed. PGF suppression by RNA interference resulted in a reduction of metastatic growth similar to that observed after GPR64 knock down. Importantly, inhibition of GPR64 as well as PGF expression was associated with a reduced expression of matrix metalloproteinase (MMP) 1 and invasiveness in vitro. Furthermore, MMP1 knock down abrogated lung metastasis in Rag2/C/ mice. Thus, GPR64 expression in ES maintains an immature phenotype that is less sensitive to TRAIL-induced apoptosis and via its up-regulation of PGF and MMP1 orchestrates and promotes invasiveness and metastatic spread.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ewing Sarcoma ; G-protein Coupled Receptor ; Invasion ; Metastasis ; Matrix Metalloproteinase 1 ; Placental Growth Factor ; Slit2 ; Pbx2; Placental Growth-factor ; Peripheral Neuroectodermal Tumors ; Dna-microarrays ; Adhesion-gpcrs ; Cancer-cells ; Angiogenesis ; Survival ; Expression ; Tissues ; Family
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 0022-3417
e-ISSN 1096-9896
Zeitschrift Journal of Pathology, The
Quellenangaben Band: 230, Heft: 1, Seiten: 70-81 Artikelnummer: , Supplement: ,
Verlag Wiley
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-500300-001
PubMed ID 23338946
DOI 10.1002/path.4170
WOS ID WOS:000317434000009
Scopus ID 84876147713
Erfassungsdatum 2013-05-16
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