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

作者：Wakamatsu Toru^*; Naka Norifumi; Sasagawa Satoru; Tanaka Takaaki; Takenaka Satoshi; Araki Nobuhito; Ueda Takafumi; Nishizawa Yasuko; Yoshikawa Hideki; Itoh Kazuyuki

来源：CANCER SCIENCE, 2014, 105(9): 1124-1134.

DOI：10.1111/cas.12469

• CXCR4
• spheroid
• SS18-SSX
• synovial sarcoma
• vascular endothelial growth factor

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.

• 出版日期2014-9