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  • It has been reported that


    It has been reported that Eph/Ephrin are involved in the regulation of the tumor angiogenesis [10], [11], [12]. The distinct and specific involvement of LBH 589 and veins in tumor angiogenesis is unclear. EphrinB2 is expressed in arteries and its receptor EphB4 is expressed in veins; these molecules play a prominent role in the control of angiogenesis. It was the purpose of our study to evaluate if tumor angiogenesis is associated with a distinct formation of arteries and veins.
    Materials and methods
    Discussion In addition to the several regulators of angiogenesis including acidic and basic fibroblast growth factor (aFGF/bFGF), transforming growth factor-alpha (TGF-α), TGF-β, hepatocyte growth factor/scatter factor (HGF/SF), tumor necrosis factor-alpha (TNF-α), angiogenin, and interleukin-8 (IL-8) [1], [2], [4], [5], [10], Eph receptors and Ephrin ligands play an important role in the development of blood vessels [7]. Our results reveal that EphrinB2 in arterial and EphB4 in venous endothelium of urogenital tract tumors might contribute to their involvement in the tumor angiogenesis. It has been shown that Eph/Ephrin-interactions are involved in the regulation of the tumor angiogenesis [11] and it is shown that arteries and veins can be distinguished from each other at a molecular level. VEGF or TNF produced by tumor cells may induce the activation of Ephrins in endothelial cells [11]. VEGF signaling induces arterial vessel formation in mice, and VEGF can induce the expression of Ephrin B2 in cultured non-arterial endothelial cells [13]. In transgenic mice, overexpression of VEGF results in increased numbers of arterial-type vessels based on EphrinB2 expression, which is accompanied by a decrease in the number of venous-type endothelial cells [14]. These results may be suggested that VEGF controls arteriogenesis by activating the arterial specification signaling that subsequently blocks venous differentiation of endothelial cells. In addition, it has been shown that angiopoietin-2 can block the VEGF-mediated increase of arterial vessels [14]. The lack of angiopoietin-1 in combination with the lack of orphan receptor tyrosine kinase, TIE1, results in a specific ablation of the venous vessels [15]. The specific receptor of angiopoietin, TIE2, was identified in the venous system [16]. In the present study, we found that EphB4 receptor was selectively localized in venous endothelial cells and that its ligand EphrinB2 was selectively localized in endothelial and in smooth muscle cells of arteries. Although an increase of arterial and venous vessels was observed in all 3 types of cancer compared with normal tissue samples, the ratio of EphB4;EphrinB2 remanded constant. Eph receptors are overexpressed in various tumor types, suggesting a role of the Eph receptors in tumor progression [12]. Up-regulation of EphrinB2 has been reported in melanomas. In the present investigation, we found that staining intensities of EphrinB2 in arterial and EphB4 in venous endothelium was significantly higher in tissue samples of cancer compared with their normal controls, independent on tumor grade. The highly staining intensities of EphrinB2 and EphB4 indicate that EphrinB2 and EphB4 may be involved in the formation of new blood vessels. EphB4 and its ligand EphrinB2 have been implicated in breast cancer [17]. In breast cancer of a transgenic mouse model, the level of EphB4 expression in myoepithelial and epithelial structures correlates with the degree of tumor malignancy [17], which supports our results. The increased staining intensities of EphrinB2 and EphB4 in epithelial cells of prostate, bladder, and kidney tumors are also compatible with the suggestion that an involvement of the EphrinB2 and EphB4 in tumor epithelial cells might be associated on the tumor progression. The localization of EphrinB2 and EphB4 in the tumor epithelial cells of the cancerous tissue of kidney, bladder, and prostate support this result. This indicates that localization of the EphrinB2 and EphB4 in the tumor epithelial cells may be involved in the regulation of tumor angiogenesis by interaction of new formed vessels with the tumor epithelium.