Department of Anatomy and Cell Biology, Osaka Medical College, Japan.
BMC Med. 2010 Nov 3;8:69. doi: 10.1186/1741-7015-8-69.
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.
癌症转移是导致癌症死亡的主要原因，它受到淋巴管生成和血管生成的促进。我们最近发现的一种新的剪接变体，内源性可溶性血管内皮生长因子受体-2（esVEGFR-2），是淋巴管生成的内源性选择性抑制剂。为了评估 esVEGFR-2 的抗转移潜力，我们对鼠转移性乳腺癌进行了表达 esVEGFR-2（pesVEGFR-2）或内皮抑素（pEndo）的载体基因治疗，作为阳性对照。
将同源接种的转移性乳腺癌接受 pesVEGFR-2、pEndo 或 pVec（对照）的直接肿瘤内注射，每周一次，共六周。每次注射后对肿瘤进行体内基因电转移。
与 pVec 组相比，pesVEGFR-2 和 pEndo 组的转移死亡率要低得多。在整个研究过程中，pesVEGFR-2 和 pEndo 组的肿瘤体积明显较小。pesVEGFR-2 和 pEndo 组的淋巴结和肺转移结节的多发性明显受到抑制。此外，这些组中包括其他器官的总转移数量也减少了。然而，pesVEGFR-2 并不能减少单侧或双侧转移计数的肺、卵巢、肾脏和肾上腺转移的数量。pEndo 组的 CD34+/Lyve-1⁻ 血液微血管数量明显减少，而 pesVEGFR-2 和 pEndo 组的 CD34⁻/Lyve-1+ 淋巴管数量明显减少。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数量显著减少。pEndo 组的细胞凋亡水平明显升高，而 pesVEGFR-2 和 pEndo 组的细胞增殖率明显降低。
我们的数据表明，esVEGFR-2 可以主要抑制淋巴结转移。esVEGFR-2 的抗转移活性在治疗转移性乳腺癌方面可能具有重要的临床意义，因为淋巴结受累是癌症患者最重要的预后因素。
