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.
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.
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DOI：
10.1111/cas.12469
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发表时间：
2014-09
期刊：
影响因子：
5.7
通讯作者：
Itoh K
中科院分区：
文献类型：
--
作者：
Wakamatsu T;Naka N;Sasagawa S;Tanaka T;Takenaka S;Araki N;Ueda T;Nishizawa Y;Yoshikawa H;Itoh K
滑膜肉瘤（SS）是一种恶性软组织肿瘤，其特征是复发性染色体易位SS 18-SSX。靶向血管内皮生长因子（VEGF）的抗血管生成治疗已被批准用于软组织肉瘤，包括SS;然而，SS中肉瘤发生的VEGF信号机制尚不清楚。在这里，我们表明SS 18-SSX指导VEGF信号结果从分化到细胞生长。滑膜肉瘤细胞在球状体培养条件下以自分泌方式分泌大量VEGF。SS 18-SSX敲低改变了VEGF信号传导结果，从增殖到肾小管分化，而不影响VEGF分泌，表明VEGF信号传导在SS 18-SSX存在下促进细胞生长。因此，VEGF抑制剂阻断宿主血管生成和球体生长。同时用VEGF和趋化因子（C-X-C基序）（CXC）配体12和CXC受体4抑制剂和/或异环磷酰胺治疗在体外和体内均有效抑制肿瘤生长。SS 18-SSX引导VEGF信号从内皮分化到球状体生长，并且VEGF和CXC受体4是SS的关键治疗靶点。
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.
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