RALBP1/RLIP76 depletion in mice suppresses tumor growth by inhibiting tumor neovascularization.
RALBP1/RLIP76 depletion in mice suppresses tumor growth by inhibiting tumor neovascularization.
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DOI：
10.1158/0008-5472.can-12-0468
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发表时间：
2012-10-15
期刊：
影响因子：
11.2
通讯作者：
Goldfinger LE
中科院分区：
文献类型：
--
作者：
Lee S;Wurtzel JG;Singhal SS;Awasthi S;Goldfinger LE
RalBP 1/RLIP 76是广泛表达的多功能蛋白，其结合Ral和R-Ras小GTP酶。在小鼠中，RLIP 76是非必需的，但其消耗或阻断促进肿瘤发生并提高正常细胞和肿瘤细胞对辐射和细胞毒性药物的敏感性。然而，其支持肿瘤发生的病理生物学功能还不清楚。在这里，我们表明，RLIP 76是所需的血管生成和有效的新生血管的原发性实体瘤。在RLIP 76 −/−小鼠中，来自植入的黑色素瘤或癌细胞的肿瘤生长变钝。一种基于X射线microCT的肿瘤血管结构建模方法揭示了RLIP 76 −/−小鼠肿瘤血管生成的程度和形式的缺陷。具体而言，RLIP 76 −/−小鼠的肿瘤血管体积减少，血管数量减少，较短，比野生型小鼠更窄。此外，我们发现，血管生成钝化突变小鼠在肿瘤细胞的情况下，从这些动物中分离的内皮细胞表现出缺陷的迁移，增殖和索形成在体外。综上所述，我们的结果证实了RLIP 76是实体瘤中有效的内皮细胞功能和血管生成所必需的。
RalBP1/RLIP76 is a widely expressed multifunctional protein that binds the Ral and R-Ras small GTPases. In the mouse, RLIP76 is non-essential but its depletion or blockade promotes tumorigenesis and heightens the sensitivity of normal and tumor cells to radiation and cytotoxic drugs. However, its pathobiological functions which support tumorigenesis are not well understood. Here we show that RLIP76 is required for angiogenesis and for efficient neovascularization of primary solid tumors. Tumor growth from implanted melanoma or carcinoma cells was blunted in RLIP76−/− mice. An X-ray microCT-based method to model tumor vascular structures revealed defects in both the extent and form of tumor angiogenesis in RLIP76−/− mice. Specifically, tumor vascular volumes were diminished and vessels were fewer in number, shorter, and narrower in RLIP76−/− mice than in wild-type mice. Moreover, we found that angiogenesis was blunted in mutant mice in the absence of tumor cells, with endothelial cells isolated from these animals exhibiting defects in migration, proliferation and cord formation in vitro. Taken together, our results establish that RLIP76 is required for efficient endothelial cell function and angiogenesis in solid tumors.