Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy
Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy
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DOI：
10.1006/mthe.2002.0533
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发表时间：
2002-02-01
影响因子：
12.4
通讯作者：
Nukiwa, T
中科院分区：
文献类型：
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作者：
Maemondo, M;Narumi, K;Nukiwa, T
肝细胞生长因子（HGF）影响肿瘤生长/侵袭和肿瘤新生血管形成。提出的HGF拮抗剂NK 4（HGF的氨基末端kringle结构域肽）通过HGF与其受体c-Met结合的竞争来抑制肿瘤生长/侵袭，并作为血管生成抑制剂。为了研究NK 4基因转移的体内效应，我们构建了表达人NK 4的腺病毒载体（AdCMV. NK 4）。用AdCMV. NK 4体外感染人肺癌细胞系（A549和H358）产生NK 4蛋白，而细胞生长速率没有变化。与此相反，将AdCMV.NK4（1 × 10（9）pfu，两次）直接注射到BALB/c nu/nu小鼠的皮下肿瘤中，与对照组相比，A549的肿瘤抑制率为64%，H358的肿瘤抑制率为91%（分别为P < 0.02或P < 0.01）。肿瘤血管计数显示，当使用AdCMV.NK4时，H358肿瘤中的血管分布被抑制了57%（P < 0.0001）。此外，通过腹膜内注射AdCMV.NK4的全身性NK 4递送有效地抑制了基质胶测定中的血管生成（86%减少，P < 0.032）、体内皮下肿瘤生长（对于H358为65%，P < 0.001）和血源性肺转移，而没有明显的副作用。这些结果表明，NK 4通过其抗血管生成活性和抗HGF活性在体内增强肿瘤生长抑制，并且NK 4基因转移可以是治疗癌症的有效工具。
Hepatocyte growth factor (HGF) affects tumor growth/invasion and tumor neovascularization. A proposed HGF antagonist, NK4 (an amino-terminal kringle-domain peptide of HGF), inhibits tumor growth/invasion through the competition of HGF binding to its receptor, c-Met, and acts as an angiogenesis inhibitor. To investigate the in vivo effect of NK4 gene transfer, we constructed an adenovirus vector expressing human NK4 (AdCMV.NK4). Human lung cancer cell lines (A549 and H358) infected in vitro with AdCMV.NK4 yielded NK4 protein without a change in the cell growth rate. In contrast, direct injection of AdCMV.NK4 (1 x 10(9) pfu, twice) into established subcutaneous tumors in BALB/c nu/nu mice resulted in suppression of the tumors by 64% for A549 or by 91% for H358 compared with controls (P < 0.02 or P < 0.01, respectively). Counting of the tumor vessels revealed suppressed vascularity by 57% in H358 tumors when using AdCMV.NK4 (P < 0.0001). Furthermore, systemic NK4 delivery by intraperitoneal injection of AdCMV.NK4 effectively suppressed both angiogenesis in the Matrigel assay (86% reduction, P < 0.032), subcutaneous tumor growth in vivo (by 65% for H358, P < 0.001), and hematogenous lung metastases without obvious side effects. These results indicate that NK4 elicits tumor-growth suppression in vivo through its anti-angiogenic activity and anti-HGF activity and that NK4 gene transfer can be an effective tool in the treatment of cancer.