Multiple roles for the receptor tyrosine kinase Axl in tumor formation
Multiple roles for the receptor tyrosine kinase Axl in tumor formation
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DOI：
10.1158/0008-5472.can-05-0993
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发表时间：
2005-10-15
期刊：
影响因子：
11.2
通讯作者：
Lorens, JB
中科院分区：
文献类型：
--
作者：
Holland, SJ;Powell, MJ;Lorens, JB
当代癌症治疗发展的焦点是靶向转化细胞和支持细胞微环境。细胞迁移是肿瘤发展所必需的多种细胞类型之间复杂相互作用所需的基本细胞行为。因此，我们开发了一种新的逆转录病毒为基础的筛选技术，在原代人内皮细胞中发现控制细胞迁移的基因。我们确定了受体酪氨酸激酶Ax1作为一种新的调节内皮细胞haptotactic迁移向基质因子玻连蛋白。使用小干扰RNA介导的沉默和野生型或突变的受体蛋白的过表达，我们表明AA是多种血管生成行为的关键调节因子，包括体外内皮细胞迁移、增殖和管形成。此外，使用持续的，逆转录病毒递送短发夹RNA（shRNA）Ax1敲低，我们表明，Ax1是必要的在小鼠模型中的体内血管生成。此外，我们表明，Ax1也需要人类乳腺癌细胞在体内形成肿瘤。这些发现表明Ax1调节对新血管形成和肿瘤发生至关重要的过程。因此，使用小分子抑制剂破坏Ax1信号传导将同时影响肿瘤和基质细胞区室，因此代表了癌症治疗开发的独特方法。
A focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Ax1 as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA-mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that AA is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Ax1 knockdown, we show that Ax1 is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Ax1 is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Ax1 regulates processes vital for both neovascularization and tumorigenesis. Disruption of Ax1 signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development.