Effect of Tumor-Specific Leukocyte Behavior on Tumor Growth

利用作者开发的实验肿瘤模型，对肠系膜微血管的血管生成过程和新形成的微血管的血流动力学进行了活体显微镜观察。在该模型中，显微镜下观察到肿瘤生长并伴有明显的血管生成，持续时间长达10天。肿瘤肠系膜的微血管长度明显增加。在新形成的肿瘤血管中，与正常肠系膜小静脉相比，白细胞在小静脉中的滚动和粘附都减弱。为了阐明这些血流动力学改变的机制，我们研究了一氧化氮（NO）在肿瘤微循环中调节白细胞动力学的作用。抑制NO合成酶（NOS）可显著增加肿瘤小静脉中白细胞-内皮细胞相互作用基线水平的降低。在无瘤大鼠和荷瘤大鼠的正常微血管中均未发现这些增加。这些结果表明，肿瘤组织中NO的过量产生创造了肿瘤特异性微环境，从而调节了血管生成肿瘤血管中的白细胞行为。

Using an experimental tumor model developed by the authors, intravital microscopic observations of the angiogenic processes in the mesenteric microvasculature and the hemodynamics of the newly formed microvessels were performed. In this model, tumor growth accompanying a marked angiogenesis was microscopically observable for up to 10 days. The length of the microvessels showed a significant increase in the tumor-bearing mesentery. In the newly formed tumor vessels, rolling and adherence of leukocytes in venules were both attenuated as compared with those in the normal mesenteric venules. To elucidate the mechanisms of these altered behavior of hemodynamics, the role of nitric oxide (NO) in regulating leukocyte dynamics in the tumor microcirculation was examined. Reduction of the baseline levels of leukocyte-endothelial cell interactions observed in the tumor venules were markedly increased by inhibition of NO synthase (NOS). These increases were neither found in the tumor-free rats nor in normal microvessels of the tumor-bearing rats. These results suggest that an excessive production of NO in the tumor tissues creates the tumor-specific microenvironment, thereby modulating leukocyte behavior in the angiogenic tumor vessels.