VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer.
VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer.
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DOI：
10.1158/0008-5472.can-10-2527
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发表时间：
2011-07-15
期刊：
影响因子：
11.2
通讯作者：
McDonald DM
中科院分区：
文献类型：
--
作者：
You WK;Sennino B;Williamson CW;Falcón B;Hashizume H;Yao LC;Aftab DT;McDonald DM
阻断血管内皮生长因子受体（VEGFR）信号传导的血管生成抑制剂减缓许多类型肿瘤的生长，但最终疾病进展。正在探索多种策略，以通过同时抑制其他功能相关的受体酪氨酸激酶（RTK）来提高疗效。XL 880（foretinib，GSK 1363089）和XL 184（cabozantinib）是小分子抑制剂，可有效阻断多种RTK，包括VEGFR和肝细胞生长因子c-Met受体，可驱动肿瘤侵袭和转移。本研究比较了XL 880和XL 184与阻断VEGFR但不阻断c-Met的RTK抑制剂（XL 999）的细胞效应。用XL 999处理RIP-Tag 2小鼠导致自发性胰岛肿瘤的血管分布在7天内减少43%，但用XL 880或XL 184处理消除了约80%的肿瘤血管，减少了周细胞和空基底膜袖，引起广泛的瘤内缺氧和肿瘤细胞凋亡，并减缓了停药后肿瘤血管的再生长。重要的是，XL 880和XL 184还降低了原发性肿瘤的侵袭性并减少了转移。总体而言，这些发现表明c-Met和功能相关激酶的抑制放大了VEGFR阻断的作用，并导致肿瘤血管系统的快速、稳健和进行性消退，增加了肿瘤内缺氧和凋亡，并降低了肿瘤侵袭和转移。
Angiogenesis inhibitors that block vascular endothelial growth factor receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTKs). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small molecule inhibitors that potently block multiple RTKs including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 to those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated ~ 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis.