Tumor angiogenesis is essential for tumor progression and the development of metastases. The angiogenic cascade starts with activation of endothelial cells by angiogenic growth factors, resulting in extracellular matrix degradation, endothelial cell migration, proliferation and tube formation, and, eventually, maturation of the blood vessel. During this multistep process, angiogenic stimulation changes endothelial cell gene expression profiles. Analysis of differentially expressed genes in tumor endothelial cell versus normal, quiescent endothelium can lead to a better understanding of endothelial cell biology during tumor angiogenesis and to the identification of tumor endothelial cell-specific markers for vascular targeting approaches.
Epigenetic processes play a major role in regulation of gene expression by affecting chromatin structure. DNA methylation and histone modifications are important mediators of epigenetic gene silencing and are essential in diverse biological processes. In cancer cells, aberrant promoter CpG island hypermethylation and histone modifications result in inappropriate transcriptional silencing of tumor-suppressor genes . DNA methyltransferase (DNMT) and histone deacety lase (HDAC) inhibitors can synergistically reactivate epigenetically silenced tumor-suppressor genes and cause growth arrest and apoptosis of tumor cells. Microarray-based strategies combining gene expression status and pharmacologic reversal of epigenetic repression have been shown powerful for identification of new epigenetically silenced tumorsuppressor genes in human cancers.
[Cancer Research, 2007; 67(9):4138-4148]
参考译文
在肿瘤形成和转移中，肿瘤血管的发生是必不可少的。正常血管的发生起始于血管源性生长因子介导的内皮细胞的活化，使得细胞外基质降解、内皮细胞迁移、增殖并形成管状物，最后血管形成。在血管形成的这一多步骤进程中，来自新生血管的刺激改变了内皮细胞的基因表达方式。通过分析肿瘤内皮细胞和正常的处于静止状态的细胞的差异表达基因，可以更好的理解内皮细胞在肿瘤血管发生中的生物学作用，并为血管靶向治疗提供肿瘤内皮细胞的特异性标志。
在基因表达调控中，表达遗传机制(通过影响染色质结构调控基因表达)发挥了重要的作用。DNA甲基化和组蛋白修饰是基因发生表达沉默的重要环节，它们在多种生物学行为的发生过程中是必不可少的。在肿瘤细胞中，启动子CpG岛的异常甲基化和组蛋白修饰会使肿瘤抑制基因在抑制转录过程时发生异常。DNA甲基化转移酶(DNMT)和组蛋白去乙酰化酶(HDAC)抑制剂可通过表达遗传机制发挥协同作用，使沉默的肿瘤抑制基因重新活化，从而使肿瘤细胞生长停滞和发生凋亡。在鉴定人类新的肿瘤抑制基因中，微阵列策略、基因表达工程及药理学上对表达抑制的逆转作用，已经显示出其强大的作用。
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