Development of novel target therapy for soft tissue sarcoma stem cells

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VEGF-targeting anti-angiogenic therapy has been approved for soft-tissue sarcoma, including synovial sarcoma (SS); however, the mechanism underlying VEGF signal for sarcomagenesis in SS is unclear. Here, we show that SS fusion gene :SS18-SSX directs the VEGF signal outcome to cellular growth from differentiation. SS 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 CXCL12/CXCR4 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 CXCR4 are critical therapeutic targets for SS.