Parker Belinda S, Argani Pedram, Cook Brian P, Liangfeng Han, Chartrand Scott D, Zhang Mindy, Saha Saurabh, Bardelli Alberto, Jiang Yide, St Martin Thia B, Nacht Mariana, Teicher Beverly A, Klinger Katherine W, Sukumar Saraswati, Madden Stephen L
Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Cancer Res. 2004 Nov 1;64(21):7857-66. doi: 10.1158/0008-5472.CAN-04-1976.
The molecular signature that defines tumor microvasculature will likely provide clues as to how vascular-dependent tumor proliferation is regulated. Using purified endothelial cells, we generated a database of gene expression changes accompanying vascular proliferation in invasive breast cancer. In contrast to normal mammary vasculature, invasive breast cancer vasculature expresses extracellular matrix and surface proteins characteristic of proliferating and migrating endothelial cells. We define and validate the up-regulated expression of VE-cadherin and osteonectin in breast tumor vasculature. In contrast to other tumor types, invasive breast cancer vasculature induced a high expression level of specific transcription factors, including SNAIL1 and HEYL, that may drive gene expression changes necessary for breast tumor neovascularization. We demonstrate the expression of HEYL in tumor endothelial cells and additionally establish the ability of HEYL to both induce proliferation and attenuate programmed cell death of primary endothelial cells in vitro. We also establish that an additional intracellular protein and previously defined metastasis-associated gene, PRL3, appears to be expressed predominately in the vasculature of invasive breast cancers and is able to enhance the migration of endothelial cells in vitro. Together, our results provide unique insights into vascular regulation in breast tumors and suggest specific roles for genes in driving tumor angiogenesis.
定义肿瘤微血管系统的分子特征可能会为血管依赖性肿瘤增殖的调控方式提供线索。我们利用纯化的内皮细胞，建立了一个伴随浸润性乳腺癌血管增殖的基因表达变化数据库。与正常乳腺血管系统相比，浸润性乳腺癌血管系统表达增殖和迁移的内皮细胞所特有的细胞外基质和表面蛋白。我们定义并验证了乳腺肿瘤血管中VE-钙黏蛋白和骨连接蛋白的上调表达。与其他肿瘤类型不同，浸润性乳腺癌血管系统诱导了包括SNAIL1和HEYL在内的特定转录因子的高表达水平，这些转录因子可能驱动乳腺肿瘤新生血管形成所需的基因表达变化。我们证明了HEYL在肿瘤内皮细胞中的表达，并进一步证实了HEYL在体外既能诱导原代内皮细胞增殖又能减弱其程序性细胞死亡的能力。我们还证实，另一种细胞内蛋白以及先前定义的转移相关基因PRL3似乎主要在浸润性乳腺癌的血管系统中表达，并且能够在体外增强内皮细胞的迁移。总之，我们的结果为乳腺肿瘤中的血管调控提供了独特的见解，并表明了基因在驱动肿瘤血管生成中的特定作用。
