title: Deflection of vascular endothelial growth factor action by SS18-SSX and composite vascular endothelial growth factor- and chemokine (C-X-C motif) receptor 4-targeted therapy in synovial sarcoma.
abstract: Synovial sarcoma (SS) is a malignant soft-tissue tumor characterized by the recurrent chromosomal translocation SS18-SSX. Vascular endothelial growth factor (VEGF)-targeting anti-angiogenic therapy has been approved for soft-tissue sarcoma, including SS; however, the mechanism underlying the VEGF signal for sarcomagenesis in SS is unclear. Here, we show that SS18-SSX directs the VEGF signal outcome to cellular growth from differentiation. Synovial sarcoma cells secrete large amounts of VEGF under spheroid culture conditions in autocrine fashion. SS18-SSX knockdown altered the VEGF signaling outcome, from proliferation to tubular differentiation, without affecting VEGF secretion, suggesting that VEGF signaling promoted cell growth in the presence of SS18-SSX. Thus, VEGF inhibitors blocked both host angiogenesis and spheroid growth. Simultaneous treatment with VEGF and chemokine (C-X-C motif) (CXC) ligand 12 and CXC receptor 4 inhibitors and/or ifosfamide effectively suppressed tumor growth both in vitro and in vivo. SS18-SSX directs the VEGF signal outcome from endothelial differentiation to spheroid growth, and VEGF and CXC receptor 4 are critical therapeutic targets for SS.
authors: Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; Department of Orthopedics, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors: Toru
authors: T
authors: Wakamatsu
authors: Norifumi
authors: N
authors: Naka
authors: Satoru
authors: S
authors: Sasagawa
authors: Takaaki
authors: T
authors: Tanaka
authors: Satoshi
authors: S
authors: Takenaka
authors: Nobuhito
authors: N
authors: Araki
authors: Takafumi
authors: T
authors: Ueda
authors: Yasuko
authors: Y
authors: Nishizawa
authors: Hideki
authors: H
authors: Yoshikawa
authors: Kazuyuki
authors: K
authors: Itoh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013584:Sarcoma, Synovial / Q000097:blood / Q000098:blood supply / Q000188:drug therapy*; D018874:Spheroids, Cellular / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C527276:CXCR4 protein, human; D015514:Oncogene Proteins, Fusion; D019718:Receptors, CXCR4; C587877:SS18-SSX1 fusion protein; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D007069:Ifosfamide
keywords: CXCR4; SS18-SSX; spheroid; synovial sarcoma; vascular endothelial growth factor