Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis
Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis
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靶向 Slit-Roundabout 信号抑制化学诱导鳞状细胞癌变中的肿瘤血管生成
DOI：
10.1111/j.1349-7006.2007.00721.x
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发表时间：
2008-03-01
期刊：
影响因子：
5.7
通讯作者：
Geng, Jian-Guo
中科院分区：
文献类型：
--
作者：
Wang, Li-Jing;Zhao, Yuan;Geng, Jian-Guo
Slit是一种分泌蛋白，已知通过Roundabout （Robo）受体发挥作用，作为轴突引导和神经元迁移的排斥剂，并作为白细胞趋化性的抑制剂。我们之前已经证明，Slit2也由多种人类癌细胞分泌，因此它作为肿瘤血管生成的血管内皮细胞的化学引诱剂。我们使用一种阻断抗体来研究在口腔癌发生过程中，Slit-Robo信号在肿瘤血管生成中的作用。在本报告中，我们在仓鼠颊袋中建立了7,12-二甲基-1,2-苯并蒽诱导的多阶段鳞状细胞癌模型。R5是一种针对Robo1第一免疫球蛋白结构域的单克隆抗体，用于研究R5是否阻断了Slit-Robo相互作用，进而抑制了我们模型中的肿瘤血管生成和生长。应用口腔鳞状细胞癌人口腔颊黏膜组织检测Slit2、von Willebrand因子、血管内皮生长因子的表达。我们的数据显示，Slit2在仓鼠颊袋正常和增生性粘膜中表达最低，在发育不良粘膜中表达中等，在肿瘤粘膜中表达较高。我们还发现，Slit2表达的增加与肿瘤血管生成的增加有关，这反映在血管内皮生长因子表达和微血管密度的增加上。在人体组织中也发现了类似的Slit2表达谱。重要的是，在我们的体内模型中，使用R5中断Slit2-Robo相互作用抑制了肿瘤血管生成和生长，这表明slit2介导的肿瘤血管生成是化学诱导的鳞状细胞癌发生的关键过程。因此，靶向Slit-Robo信号可能为口腔癌治疗提供一种新的抗血管生成方法。
Slit is a secreted protein known to function through the Roundabout (Robo) receptor as a repellent for axon guidance and neuronal migration, and as an inhibitor in leukocyte chemotaxis. We have previously shown that Slit2 is also secreted by a variety of human cancer cells whereby it acts as a chemoattractant to vascular endothelial cells for tumor angiogenesis. We used a blocking antibody to investigate the role of Slit-Robo signaling in tumor angiogenesis during oral carcinogenesis. In this report we undertook a multistage model of 7,12-dimethyl-1,2-benzanthracene-induced squamous cell carcinoma in the hamster buccal pouch. R5, a monoclonal antibody against the first immunoglobulin domain of Robo1, was used to study whether R5 blocks the Slit-Robo interaction and furthermore inhibits tumor angiogenesis and growth in our model. In addition, the expression of Slit2, von Willebrand factor, and vascular endothelial growth factor were examined using human tissue of oral cheek mucosa with oral squamous cell carcinoma. Our data showed that Slit2 was expressed minimally in normal and hyperplastic mucosa, moderately in dysplastic mucosa, and highly in neoplastic mucosa obtained from hamster buccal pouch. We also found that increased Slit2 expression was associated with higher tumor angiogenesis, as reflected by increased vascular endothelial growth factor expression and microvessel density. A similar Slit2 expression profile was found in human tissue. Importantly, interruption of the Slit2-Robo interaction using R5 inhibited tumor angiogenesis and growth in our in vivo model, which indicates that Slit2-mediated tumor angiogenesis is a critical process underlying the carcinogenesis of chemical-induced squamous cell carcinoma. Therefore, targeting Slit-Robo signaling may offer a novel antiangiogenesis approach for oral cancer therapy.