Suppression of VEGFR‐3 signaling inhibits lymph node metastasis in gastric cancer
Suppression of VEGFR‐3 signaling inhibits lymph node metastasis in gastric cancer
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DOI：
10.1111/j.1349-7006.2004.tb03211.x
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发表时间：
2004-04
期刊：
影响因子：
5.7
通讯作者：
K. Shimizu;H. Kubo;K. Yamaguchi;K. Kawashima;Y. Ueda;Koichi Matsuo;M. Awane;Y. Shimahara;
中科院分区：
文献类型：
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作者：
K. Shimizu;H. Kubo;K. Yamaguchi;K. Kawashima;Y. Ueda;Koichi Matsuo;M. Awane;Y. Shimahara;
在胃癌中，淋巴结转移是影响预后的主要因素之一，也是手术切除局部淋巴结的基础。近年来，多项研究表明，在小鼠肿瘤模型中过表达淋巴管生长因子VEGF-C或VEGF-D可诱导肿瘤淋巴管生成并促进淋巴转移。我们研究了在自然转移的肿瘤中，是否可以通过阻断它们的同源受体VEGFR-3信号通路来抑制这些过程。利用高转移率的小鼠原位胃癌模型，通过VEGFR-3和其他特异性淋巴标志物LYVE-1和PROX-1的免疫组织化学染色，估计胃癌中的淋巴管，然后系统地应用抗VEGFR-3阻断抗体。治疗可抑制原发灶的区域淋巴结转移，减少淋巴管密度。此外，在人的胃癌标本中，原发肿瘤LYVE-1阳性淋巴管密度的增加与淋巴结转移密切相关。通过抑制VEGFR-3信号通路抑制淋巴管生成，为预防胃癌的淋巴转移提供了一种潜在的策略。
In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF‐C or VEGF‐D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR‐3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR‐3 and other specific lymphatic markers, LYVE‐1 and prox‐1. Then we systemically administered anti‐VEGFR‐3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE‐1‐positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR‐3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.