Analysis of Tumor-associated Endothelial Cell Biology

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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.