Journal Article

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

Wakamatsu, Toru, Sasagawa, Satoru, Ueda, Takafumi, Itoh, Kazuyuki, Araki, Nobuhito, Tanaka, Takaaki, Nishizawa, Yasuko, Naka, Norifumi, Takenaka, Satoshi, Yoshikawa, Hideki

2014

Overview

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. This study showed link between SS18‐SSX and VEGF signal contributing tumor growth, and presented novel combined therapeutic approach on synovial sarcoma.

• Publisher: BlackWell Publishing Ltd
• Subject: Angiogenesis Inhibitors - pharmacology / Animals / Antibodies, Monoclonal, Humanized - pharmacology / Bevacizumab / Cell Line, Tumor / Cell Proliferation - drug effects / CXCR4 / Drug Synergism / Gene Knockdown Techniques / Humans / Ifosfamide - pharmacology / Mice / Mice, Inbred BALB C / Mice, Nude / Molecular Targeted Therapy / Neovascularization, Pathologic - drug therapy / Oncogene Proteins, Fusion - physiology / Original / Receptors, CXCR4 - antagonists & inhibitors / Receptors, CXCR4 - metabolism / Sarcoma, Synovial - blood / Sarcoma, Synovial - blood supply / Sarcoma, Synovial - drug therapy / spheroid / Spheroids, Cellular - metabolism / SS18–SSX / synovial sarcoma / vascular endothelial growth factor / Vascular Endothelial Growth Factor A - blood / Vascular Endothelial Growth Factor Receptor-2 - blood / Xenograft Model Antitumor Assays