水通道 AQP1 敲除小鼠肿瘤血管生成障碍及肿瘤生长减缓

血管生成是肿瘤生长、浸润和转移的必要步骤. 肿瘤血管生成涉及瘤旁组织血管内皮细胞增殖、向肿瘤细胞团内迁移以及管腔形成，目前机理尚不完全清楚. 水通道 AQP1 在多种肿瘤血管内皮高表达，提示其可能参与肿瘤血管的生成过程. 应用 AQP1 敲除小鼠荷瘤实验证实了 AQP1 在黑色素瘤生长和血管新生中的作用. 结果表明，皮下接种的黑色素瘤在 AQP1 敲除小鼠的生长较之在野生型小鼠延迟近 30％ (P<0.01). 免疫组化与肿 瘤病理形态学分析显示， AQP1 在野生型小鼠黑色素瘤血管内皮细胞上高表达，而在 AQP1 敲除小鼠黑色素瘤血管内皮细胞呈阴性表达. 在病理结构上，黑色素瘤细胞围绕血管分支呈岛状分布. 野生型小鼠黑色素瘤内血管管腔较细小，而 AQP1(－/－)小鼠黑色素瘤内血管床显著膨大. AQP1(－/－)小鼠肿瘤内平均微血管密度 (47/mm²) 较之 AQP1(＋/＋) 肿瘤 (142/mm²) 减少 67％ (P<0.01). 围绕 AQP1(－/－) 肿瘤血管的肿瘤细胞岛周边坏死区域明显大于 AQP1(＋/＋)肿瘤. 上述结果提出确切证据表明， AQP1 缺失使肿瘤血管生成发生障碍，从而影响了肿瘤血液供应和肿瘤生长. AQP1参与肿瘤血管生成的机理值得深入研究.

Defective Tumor Angiogenesis and Retarded Tumor Growth in Aquaporin-1 Knockout Mice

Tumor angiogenesis is a mandatory step of tumor growth, invasion, and metastasis involving endothelial cell proliferation and migration from blood vessels in peritumoral tissues and formation of tubules. Water channel aquaporin-1 (AQP1) has been reported to express in microvessels of many different type of tumors, indicating the possible involvement of AQP1 in tumor angiogenesis. A melanoma-bearing model in AQP1-knockout mice was used to evaluate the role of AQP1 in tumor angiogenesis. The results demonstrated nearly 30% retarded growth of subcutaneously inoculated melanoma in AQP1 knockout mice compared to tumors in wildtype mice. Immunohistochemistry of melanoma sections revealed strong AQP1 protein labeling in endothelium of tumor blood vessels in wildtype mice and negative labeling of AQP1 in the counterpart structures in AQP1-knockout mice. On the same tumor sections stained by hematoxylin, melanoma cells form islands with microvessels in the center. It is easily seen that high-density and thin microvessels (142/mm^{2) locate in the center of tumor islands in wildtype mice, whereas sparse and enlarged vessels (47/mm2) are evident in tumor islands in AQP1 knockout mice coincident with larger necrotic area in outer layer of the islands. These results provide definitive evidence that lacking of water channel AQP1 results in defective tumor angiogenesis and retarded tumor growth that may be involved in insufficient blood supply and/or abnormal transendothelial fluid transport. The underlying molecular and cellular mechanisms are worth further investigation.}