Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration
Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration
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DOI：
10.1073/pnas.0705647104
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发表时间：
2007-11-13
影响因子：
11.1
通讯作者：
Zhou, Yuhong
中科院分区：
文献类型：
--
作者：
Tomkowicz, Brian;Rybinski, Katherine;Zhou, Yuhong
Endosialin/TEM1最初被发现是一种人类胚胎成纤维细胞特异性抗原，后来发现在肿瘤间质和内皮细胞中有差异表达。内毒素/TEM1在许多不同组织来源的癌症中都有过表达，包括结肠癌、乳腺癌、胰腺癌和肺癌。基因敲除(KO)小鼠模型显示，内毒素/TEM1的表达缺失降低了人肿瘤异种移植瘤的生长、侵袭和转移。此外，缺乏内毒素/TEM1导致未成熟小血管增多，中、大肿瘤血管数量减少。这种异常的血管生成反应可能是在Endosialin/TEM1 KO小鼠中观察到的肿瘤生长和侵袭减少的原因，提示Endosialin/TEM1在控制肿瘤细胞、内皮和基质之间的相互作用中发挥作用。在这里，我们报告了纤维连接蛋白(FN)和I型和IV型胶原作为内毒素/TEM1的特异性配体的鉴定。更重要的是，表达Endosialin/TEM1的细胞表现出与FN的粘附性增强以及通过Matrigel的迁移，尽管这些特性可以被针对人Endosialin/TEM1的人源化抗体所阻断。我们的研究结果表明，肿瘤间质和血管内皮细胞中的Endosialin/TEM1的表达可能支持肿瘤的进展和侵袭。
Endosialin/TEM1 was originally discovered as a human embryonic fibroblast-specific antigen and was later found to be differentially expressed in tumor stroma and endothelium. Endosialin/TEM1 overexpression has been observed in many cancers of various tissue origin, including colon, breast, pancreatic, and lung. The knockout (KO) mouse model showed the absence of endosialin/TEM1 expression reduced growth, invasion, and metastasis of human tumor xenografts. In addition, lack of endosialin/TEM1 led to an increase in small immature blood vessels and decreased numbers of medium and large tumor vessels. This abnormal angiogenic response could be responsible for the reduced tumor growth and invasion observed in endosialin/TEM1 KO mice, suggesting a role for endosialin/TEM1 in controlling the interaction among tumor cells, endothelia, and stromal matrix. Here we report the identification of fibronectin (FN) and collagen types I and IV as specific ligands for endosialin/TEM1. More importantly, cells expressing endosialin/TEM1 exhibit enhanced adhesion to FN as well as enhanced migration through matrigel, although these properties could be blocked by a humanized antibody directed against human endosialin/TEM1. Our results pinpoint to a molecular mechanism by which expression of endosialin/TEM1 in the tumor stroma and endothelium may support tumor progression and invasion.