Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis.
Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis.
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DOI：
10.1158/0008-5472.can-08-4051
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Fukumura D
中科院分区：
文献类型：
--
作者：
Lahdenranta J;Hagendoorn J;Padera TP;Hoshida T;Nelson G;Kashiwagi S;Jain RK;Fukumura D
淋巴转移是癌症预后的关键决定因素。近年来，一些淋巴管生成分子如血管内皮生长因子（VEGF）-C和-D被鉴定出来。然而，对淋巴转移的机制的理解仍处于婴儿期。一氧化氮（NO）在调节血管生长和功能以及淋巴管功能中起着至关重要的作用。NOS表达与淋巴结转移有关。然而，NOS和淋巴转移之间的因果关系尚未被记录。为此，我们首先表明VEGF受体-2和-3刺激都会激活淋巴管内皮细胞中的eNOS，并且NO供体以剂量依赖性方式诱导培养的淋巴管内皮细胞的增殖和/或存活。我们发现一氧化氮合酶抑制剂L-NMMA阻断淋巴管再生。使用活体显微镜，使我们能够可视化淋巴转移的步骤，我们表明，eNOS基因缺失以及NOS阻断减弱VEGF-C过度表达T241纤维肉瘤的瘤周淋巴增生，并减少转移性肿瘤细胞向引流淋巴结的转移。宿主中eNOS的基因缺失也导致T241肿瘤细胞向淋巴结的播散和B16 F10黑色素瘤的肉眼淋巴结转移减少。这些发现表明eNOS介导VEGF-C诱导的淋巴管生成，因此在淋巴转移中起关键作用。我们的研究结果解释了在许多人类肿瘤中观察到的NOS和淋巴转移之间的相关性，并为利用NO信号治疗淋巴系统疾病的潜在疗法打开了大门。
Lymphatic metastasis is a critical determinant of cancer prognosis. Recently, several lymphangiogenic molecules such as vafscular endothelial growth factor (VEGF)-C and -D were identified. However, the mechanistic understanding of lymphatic metastasis is still in infancy. Nitric oxide (NO) plays a crucial role in regulating blood vessel growth and function as well as lymphatic vessel function. NOS expression correlates with lymphatic metastasis. However, causal relationship between NOS and lymphatic metastasis has not been documented. To this end, we first show that both VEGF receptor-2 and -3 stimulation activate eNOS in lymphatic endothelial cells and that NO donors induce proliferation and/or survival of cultured lymphatic endothelial cells in a dose dependent manner. We find that an NOS inhibitor L-NMMA blocked regeneration of lymphatic vessels. Using intravital microscopy that allows us to visualize the steps of lymphatic metastasis, we show that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes. Genetic deletion of eNOS in the host also leads to a decrease in T241 tumor cell dissemination to the lymph nodes and macroscopic lymph node metastasis of B16F10 melanoma. These findings indicate that eNOS mediates VEGF-C induced lymphangiogenesis and, consequently, plays a critical role in lymphatic metastasis. Our findings explain the correlation between NOS and lymphatic metastasis seen in a number of human tumors and open the door for potential therapies exploiting NO signaling to treat diseases of the lymphatic system.