Analysis of Tumor-associated Endothelial Cell Biology

肿瘤血管生成是实体瘤进展和转移的必要条件。肿瘤血管已被证明与正常血管不同，例如在形态上的变化。肿瘤血管生成的一个重要概念是，肿瘤内皮细胞被认为是基因正常的，即使这些内皮细胞在结构和功能上都是异常的。迄今为止，已经开发出许多抗血管生成药物，但其治疗效果并不显著，而且有报道称其有毒副作用。为了开发理想的抗血管生成疗法，了解肿瘤内皮细胞异常是很重要的。我们从小鼠异种肿瘤移植中分离出肿瘤内皮细胞，发现肿瘤内皮细胞异常。肿瘤内皮细胞上调许多基因，如表皮生长因子受体（EGFR）。肿瘤内皮细胞对EGF也更敏感。此外，肿瘤内皮细胞细胞遗传学异常。荧光原位杂交（FISH）分析显示，新分离的未培养的肿瘤内皮细胞即使在未培养的情况下也是非整倍体，这与目前的假设相反。与此形成鲜明对比的是，正常皮肤内皮细胞为二倍体，在培养过程中细胞遗传学保持稳定。我们得出结论，肿瘤内皮细胞在肿瘤微环境中可以获得细胞遗传学异常。最近我们分析了肿瘤内皮细胞的基因表达模式，并将其与正常内皮细胞进行了比较。我们在肿瘤内皮细胞中发现了几个上调的基因。目前正在进行进一步的研究，以调查这些肿瘤内皮细胞特异性标志物的意义。

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from their normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, even though these endothelial cells are structurally and functionally abnormal. To date, many anti-angiogenic drugs have been developed, but, their therapeutic efficacy is not dramatical and it has been also reported to cause toxic side effects. To develop ideal antiangiogenic therapies, understanding tumor endothelial cell abnormalities is important. We have isolated tumor endothelial cells from mouse tumor xenografts and have shown that tumor endothelial cells are abnormal. Tumor endothelilal cells upregulate many genes, such as epidermal growth factor receptor (EGFR). Tumor endothelilal cells are also more sensitive to EGF. Furthermore, tumor endothelial cells were cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid even when uncultured, contrary to current assumption. In marked contrast, normal skin endothelial cells were diploid and remained cytogenetically stable in culture. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment. Recently we analyzed the gene expression pattern of tumor endothelial cells and compared them to normal endothelial cells. We found the several genes which were upregulated in tumor endothelial cells. Further investigations are currently ongoing to investigate the significance of these tumor endothelial cell specific markers.