Development of novel target therapy for soft tissue sarcoma stem cells

vegf靶向抗血管生成疗法已被批准用于软组织肉瘤，包括滑膜肉瘤（SS）；然而，血管内皮生长因子信号在肉瘤发生中的作用机制尚不清楚。在这里，我们发现SS融合基因：SS18-SSX引导VEGF信号结果从分化到细胞生长。在球形培养条件下，SS细胞以自分泌方式分泌大量VEGF。SS18-SSX敲低改变了VEGF信号转导结果，从增殖到小管分化，但不影响VEGF分泌，提示在SS18-SSX存在下，VEGF信号转导促进了细胞生长。因此，VEGF抑制剂阻断了宿主血管生成和球体生长。VEGF和CXCL12/CXCR4抑制剂和/或异环磷酰胺同时治疗可有效抑制体外和体内肿瘤生长。SS18-SSX引导VEGF信号从内皮分化到球体生长，VEGF和CXCR4是SS的关键治疗靶点。

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.