Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis
Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis
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DOI：
10.1073/pnas.0508825103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Gutkind, J. Silvio
中科院分区：
文献类型：
--
作者：
Basile, John R.;Castilho, Rogerio M.;Gutkind, J. Silvio
肿瘤进展和转移取决于癌细胞启动血管生成并确保将氧气、营养物和生长因子递送至快速分裂的转化细胞并提供进入体循环的途径的能力。除了公认的促进毛细血管发芽和内皮细胞生长和迁移的生长因子和炎症介质外，新出现的证据支持轴突导向分子在调节血管发育中的先前未被认识的功能。在这里，我们表明，semaphorin 4D（Sema 4D）的蛋白质最初显示，以调节轴突生长锥的指导，在发展中的中枢神经系统，通过其受体，丛蛋白-B1，是高度表达的细胞系来源于头颈部鳞状细胞癌（HNSCCs）在蛋白质和信息水平。大量HNSCC标本的免疫组化分析显示，在转化上皮细胞的侵袭性岛屿中的细胞表面模式中，Sema 4D水平较高，但在正常和非侵袭性发育不良上皮中则不然。在前列腺癌、结肠癌、乳腺癌和肺癌组织的恶性细胞中观察到类似的模式。当从HNSCC细胞脱落时，Sema 4D刺激内皮细胞迁移，这可以通过Sema 4D阻断抗体和Sema 4D敲低来防止。此外，通过慢病毒表达Sema 4D shRNA敲低Sema 4D显著降低了HNSCC肿瘤异种移植物的大小和血管分布。这些发现表明，Sema 4D的表达是一种常用的策略，通过该策略，多种癌症可以促进血管生成，因此是治疗这些恶性肿瘤的可能的治疗靶点。
Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis and ensure delivery of oxygen, nutrients, and growth factors to rapidly dividing transformed cells and provide access to the systemic circulation. In addition to well established growth factors and inflammatory mediators that promote capillary sprouting and endothelial cell growth and migration, an emerging body of evidence supports a previously unrecognized function for axon guidance molecules in regulation of blood vessel development. Here we show that semaphorin 4D (Sema4D) a protein originally shown to regulate axonal growth cone guidance in the developing central nervous system through its receptor, plexin-B1, is highly expressed in cell lines derived from head and neck squamous cell carcinomas (HNSCCs) at both the protein and message level. Immunohistochemical analysis of a large collection of HNSCC specimens revealed high levels of Sema4D in a cell surface pattern in invading islands of transformed epithelial cells, but not in normal and noninvasive dysplastic epithelium. A similar pattern was observed in malignant cells from prostate, colon, breast, and lung cancer tissues. When shed from HNSCC cells, Sema4D stimulates endothelial cell migration, which can be prevented by Sema4D-blocking antibodies and by Sema4D knockdown. Furthermore, knocking down Sema4D by lentiviral expression of Sema4D shRNA reduces dramatically the size and vascularity of HNSCC tumor xenografts. These findings indicate that expression of Sema4D is a frequently used strategy by which a wide variety of carcinomas may promote angiogenesis, and therefore is a possible therapeutic target for the treatment of these malignancies.