The First Hospital of Jilin University, Changchun, China.
Mol Cancer Res. 2012 Aug;10(8):1021-31. doi: 10.1158/1541-7786.MCR-11-0498. Epub 2012 Jul 5.
The SDF-1/CXCR4 axis has been implicated in breast cancer metastasis. In contrast to its well-established role in organ-specific homing and colonization of tumor cells, the involvement in intravasation, especially in a hypoxic environment, is still poorly understood. Initially, we detected both, the chemokine SDF-1 and its receptor CXCR4 in microvessels in invasive ductal cancer samples. To elucidate the role of the SDF-1/CXCR4 axis in vascular endothelium for tumor intravasation, we evaluated the effects of CXCR4 activation in human umbilical vein and dermal microvascular endothelial cells (HUVEC and HDMEC) and in cultured mammary carcinoma cells (MDA MB231, and MCF7). We observed an upregulation of SDF-1 and CXCR4 in HUVECs in hypoxia, which led to proliferation, migration, and tube formation. Hypoxia induced adhesion of tumor cells to endothelial cells and stimulated transendothelial migration. The effects of hypoxia were dependent on the activity of the transcription factor hypoxia-inducible factor. Adhesion to and migration through a HUVEC monolayer were significantly reduced by lentiviral inhibition of CXCR4 in breast carcinoma cells or treatment of endothelial cells with an anti-SDF-1 neutralizing antibody. These data show that the interaction of SDF-1 secreted by ECs with tumor cell CXCR4 is sufficient to stimulate transendothelial migration of the tumor cells. Our results suggest that the SDF-1/CXCR4 axis is important in angiogenesis and tumor cell intravasation. Because both proteins were readily identifiable in a significant fraction of human breast cancer samples by immunohistochemistry, CXCR4 may constitute a molecular target for therapy when both, SDF-1, and CXCR4 are expressed.
SDF-1/CXCR4 轴被认为与乳腺癌转移有关。与它在器官特异性归巢和肿瘤细胞定植中的作用相比,其在血管内渗透中的作用,特别是在缺氧环境中的作用,仍知之甚少。最初,我们在浸润性导管癌样本的微血管中检测到趋化因子 SDF-1 和其受体 CXCR4。为了阐明 SDF-1/CXCR4 轴在血管内皮细胞中对肿瘤血管内渗透的作用,我们评估了 CXCR4 激活对人脐静脉和真皮微血管内皮细胞(HUVEC 和 HDMEC)以及培养的乳腺癌细胞(MDA MB231 和 MCF7)的影响。我们观察到 HUVEC 在缺氧条件下 SDF-1 和 CXCR4 的上调,这导致了增殖、迁移和管形成。缺氧诱导肿瘤细胞与内皮细胞的黏附,并刺激跨内皮迁移。缺氧的作用依赖于转录因子缺氧诱导因子的活性。用慢病毒抑制乳腺癌细胞中的 CXCR4 或用抗 SDF-1 中和抗体处理内皮细胞,可显著减少肿瘤细胞与 HUVEC 单层的黏附和迁移。这些数据表明,ECs 分泌的 SDF-1 与肿瘤细胞 CXCR4 的相互作用足以刺激肿瘤细胞的跨内皮迁移。我们的结果表明,SDF-1/CXCR4 轴在血管生成和肿瘤细胞血管内渗透中很重要。由于免疫组织化学分析显示,这两种蛋白在相当一部分人类乳腺癌样本中都很容易识别,因此当 SDF-1 和 CXCR4 都表达时,CXCR4 可能成为治疗的分子靶点。