A host deficiency of discoidin domain receptor 2 ( DDR2) inhibits both tumour angiogenesis and metastasis
A host deficiency of discoidin domain receptor 2 ( DDR2) inhibits both tumour angiogenesis and metastasis
复制标题
宿主缺乏盘状蛋白结构域受体 2 (DDR2) 会抑制肿瘤血管生成和转移。
DOI：
10.1002/path.4311
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发表时间：
2014-03-01
影响因子：
7.3
通讯作者：
Su, Jin
中科院分区：
文献类型：
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作者：
Zhang, Shuya;Bu, Xin;Su, Jin
盘状结构域受体2（DDR2）是一种独特的受体酪氨酸激酶（RTK），其响应于胶原结合而发出信号，并且与肿瘤恶性表型如侵袭和转移有关。尽管已有报道称DDR2表达在活化的内皮细胞（EC）中上调，但缺乏功能研究。在此，我们发现DDR2的增强表达促进了原代人脐静脉内皮细胞（HUVECs）的增殖、迁移和管腔形成。免疫组化分析结果显示，DDR2在人类肿瘤EC中的水平非常高。最重要的是，我们发现宿主缺乏DDR2抑制VEGF或肿瘤细胞诱导的皮下血管生成。此外，DDR2缺陷小鼠中剩余的肿瘤血管表现出一些标准化的特性。这些血管表型伴随着抗血管生成基因的上调和促血管生成基因的下调，以及减轻的肿瘤缺氧。通过使用黑色素瘤的尾静脉转移模型，我们发现间质DDR2的缺失也抑制肿瘤向肺的转移。因此，我们目前的数据揭示了DDR2影响肿瘤进展的新机制，并可能加强靶向DDR2作为抗癌策略的可行性。版权所有© 2013大不列颠及爱尔兰病理学会。由John Wiley & Sons有限公司出版
Discoidin domain receptor 2 (DDR2) is a unique receptor tyrosine kinase (RTK) that signals in response to collagen binding and is implicated in tumour malignant phenotypes such as invasion and metastasis. Although it has been reported that DDR2 expression is up‐regulated in activated endothelial cells (ECs), functional studies are lacking. Herein, we found that enforced expression of DDR2 promoted proliferation, migration and tube formation of primary human umbilical vein endothelial cells (HUVECs). The results of immunohistochemical analysis showed a strikingly high level of DDR2 in human tumour ECs. Most significantly, we discovered that a host deficiency of DDR2 inhibits subcutaneous angiogenesis induced by either VEGF or tumour cells. In addition, the remaining tumour vessels in DDR2‐deficient mice exhibit some normalized properties. These vascular phenotypes are accompanied by the up‐regulation of anti‐angiogenic genes and down‐regulation of pro‐angiogenic genes, as well as by alleviated tumour hypoxia. By use of a tail vein metastasis model of melanoma, we uncovered that loss of stromal DDR2 also suppresses tumour metastasis to the lung. Hence, our current data disclose a new mechanism by which DDR2 affects tumour progression, and may strengthen the feasibility of targeting DDR2 as an anticancer strategy. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.