Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model
Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model
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DOI：
10.1038/cgt.2008.43
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发表时间：
2008-12-01
影响因子：
6.4
通讯作者：
Otsuki, Y.
中科院分区：
文献类型：
--
作者：
Shibata, M-A;Morimoto, J.;Otsuki, Y.
肿瘤转移对癌症死亡率有重要影响，并受淋巴管生成和血管生成的促进。血管内皮生长因子- c （VEGF-C）和VEGF-A参与淋巴管生成和血管生成。为了抑制转移，我们对小鼠转移性乳腺癌进行了靶向VEGF-C和/或VEGF-A的载体小干扰RNA （siRNA）联合治疗。同基因、接种的转移性乳腺癌接受肿瘤内直接注射靶向VEGF-C （psiRNA-VEGF-C）、VEGF-A （psiRNA-VEGF-A）、VEGF-C和VEGF-A （psiRNA-VEGF-C和psiRNA-VEGF-A注射载体，称为psiRNA-VEGF-C+A组）或无序序列（psiRNA-SCR）作为对照，每周1次，持续8周。每次注射后对肿瘤进行基因电转移。在整个研究过程中，psiRNA-VEGF-A组和psiRNA-VEGF-C+A组的肿瘤体积显著降低。在所有治疗组中，淋巴结转移的发生率均显著降低，而仅在psiRNA-VEGF-C+A组中，肺转移的多样性显著降低。所有siRNA治疗组均显示含有腔内癌细胞的扩张淋巴管数量和微血管密度显著减少。我们的数据表明，特异性沉默VEGF-C或VEGF-A基因可以抑制淋巴结转移。然而，靶向VEGF-C和VEGF-A的siRNA联合治疗可以抑制淋巴结和肺转移，使得这种联合治疗比单独治疗更有益。观察到靶向VEGF-C或VEGF-A的sirna表达载体的抗转移活性，可能在转移性乳腺癌的治疗中具有很高的临床意义。
Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. Vascular endothelial growth factor-C (VEGF-C) and VEGF-A are involved in lymphangiogenesis and angiogenesis. To inhibit metastasis, combination therapy with vector-based small interfering RNA (siRNA) against VEGF-C and/or VEGF-A was conducted on murine metastatic mammary cancer. Syngeneic, inoculated, metastatic mammary cancers received direct intratumoral injection of plasmid siRNA vector targeting VEGF-C (psiRNA-VEGF-C), VEGF-A (psiRNA-VEGF-A), both VEGF-C and VEGF-A (both psiRNA-VEGF-C and psiRNA-VEGF-A vectors injected, referred to as the psiRNA-VEGF-C+A group) or a scrambled sequence (psiRNA-SCR) as control, once a week for 8 weeks. Gene electrotransfer was performed on the tumors after each injection. Tumor volume was significantly lower in the psiRNA-VEGF-A and the psiRNA-VEGF-C+A groups throughout the study. Lymph node metastasis was significantly less frequent in all therapeutic groups, whereas the multiplicity of lung metastases was significantly lower in the psiRNA-VEGF-C+A group only. All siRNA therapeutic groups showed a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells and microvessel density. Our data suggest that specific silencing of the VEGF-C or VEGF-A gene alone can inhibit lymph node metastasis. However, combination siRNA therapy targeting both VEGF-C and VEGF-A inhibits both lymph node and lung metastasis, rendering this combined therapy more beneficial than either alone. The observed anti-metastatic activity of siRNA-expressing vectors targeting VEGF-C or VEGF-A may be of high clinical significance in the treatment of metastatic breast cancer.