The endogenous soluble VEGF receptor-2 isoform suppresses lymph node metastasis in a mouse immunocompetent mammary cancer model.
The endogenous soluble VEGF receptor-2 isoform suppresses lymph node metastasis in a mouse immunocompetent mammary cancer model.
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DOI：
10.1186/1741-7015-8-69
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发表时间：
2010-11-03
期刊：
影响因子：
9.3
通讯作者：
Otsuki Y
中科院分区：
文献类型：
--
作者：
Shibata MA;Ambati J;Shibata E;Albuquerque RJ;Morimoto J;Ito Y;Otsuki Y
肿瘤转移是导致癌症死亡率的重要因素，淋巴管生成和血管生成促进了肿瘤转移。我们最近发现的一种新的剪接变异体--内源性可溶性血管内皮生长因子受体-2(esVEGFR-2)是一种内源性选择性淋巴管生成抑制因子。为了评价esVEGFR-2的抗转移潜能，以表达esVEGFR-2的载体(PesVEGFR-2)或内皮抑素(Pendo)为阳性对照，对小鼠转移性乳腺癌进行了基因治疗。同基因转移性乳腺癌直接瘤内注射PesVEGFR-2、Pendo或pVEC作为对照，每周1次，连续6周。每次注射后对肿瘤进行体内基因电转移。PesVEGFR-2和Pendo组的转移死亡率比pVEC组低得多。在整个研究过程中，PesVEGFR-2和Pendo组的肿瘤体积明显较小。PesVEGFR-2组和Pendo组的淋巴结节和肺转移结节的多样性明显受到抑制。此外，包括其他器官在内的总转移数在这些组中也减少了。但PesVEGFR-2不能减少单侧或双侧转移的肺、卵巢、肾和肾上腺的转移数目。Pendo组CD34+/Lyve-1-微血管数显著减少，而PesVEGFR-2和Pendo组CD34-/LYVE-1+淋巴管数显著减少。此外，在PesVEGFR-2和Pendo组中观察到含有腔内癌细胞的扩张淋巴管的数量显著减少。Pendo组的细胞凋亡率显著增加，而PesVEGFR-2和Pendo组的细胞增殖率显著降低。我们的研究结果表明，esVEGFR-2主要抑制淋巴转移。EsVEGFR-2的抗转移活性可能在转移性乳腺癌的治疗中具有很高的临床意义，因为淋巴转移是癌症患者最重要的预后因素。
Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. A new splicing variant, endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2) that we recently identified is an endogenous selective inhibitor of lymphangiogenesis. To evaluate the antimetastatic potential of esVEGFR-2, gene therapy with vector expressing esVEGFR-2 (pesVEGFR-2) or endostatin (pEndo) as a positive control was conducted on murine metastatic mammary cancer. Syngeneic inoculated metastatic mammary cancers received direct intratumoral injection of pesVEGFR-2, pEndo or pVec as control, once a week for six weeks. In vivo gene electrotransfer was performed on the tumors after each injection. Deaths from metastasis were much lower in the pesVEGFR-2 and pEndo groups than in those of the pVec. Tumor volume was significantly lower in the pesVEGFR-2 and the pEndo groups throughout the study. Multiplicity of lymph node and lung metastatic nodules was significantly suppressed in the pesVEGFR-2 and pEndo groups. Moreover, the total number of overall metastasis including the other organs was also decreased in these groups. However, pesVEGFR-2 was not able to decrease the number of lungs, ovaries, kidneys and adrenals with metastasis as counted by unilateral or bilateral metastasis. The number of CD34+/Lyve-1- blood microvessels was significantly decreased in the pEndo group, while the number of CD34-/Lyve-1+ lymphatic vessels was significantly decreased in the pesVEGFR-2 and pEndo groups. In addition, a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells was observed in the pesVEGFR-2 and pEndo groups. Levels of apoptosis were significantly increased in the pEndo group, whereas the rates of cell proliferation were significantly decreased in the pesVEGFR-2 and pEndo groups. Our data demonstrate that esVEGFR-2 can inhibit mainly lymph node metastasis. The antimetastatic activity of esVEGFR-2 may be of high clinical significance in the treatment of metastatic breast cancer because lymph node involvement is a most important prognostic factor in cancer patients.
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DOI：
10.1093/jnci/94.11.819
发表时间：
2002-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
He, YL;Kozaki, KI;Alitalo, K
通讯作者：
Alitalo, K
影响因子：
11.2
作者：
Hoshida, Tohru;Isaka, Naohide;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
11.5
作者：
Kodama, Michiyo;Kitadai, Yasuhiko;Chayama, Kazuaki
通讯作者：
Chayama, Kazuaki
影响因子：
4.8
作者：
Kim, YM;Hwang, S;Kwon, YG
通讯作者：
Kwon, YG
影响因子：
11.2
作者：
Burton JB;Priceman SJ;Sung JL;Brakenhielm E;An DS;Pytowski B;Alitalo K;Wu L
通讯作者：
Wu L