NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor
NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor
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DOI：
10.1182/blood-2006-02-003103
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Ikeda, Yasuo
中科院分区：
文献类型：
--
作者：
Du, Wenlin;Hattori, Yutaka;Ikeda, Yasuo
肝细胞生长因子（HGF）促进细胞生长和运动，也增加新血管形成。多发性骨髓瘤（MM）细胞产生HGF，临床活动性MM患者血浆中HGF浓度显著升高，提示HGF可能在MM的发病机制中发挥作用。NK 4是一种HGF拮抗剂，与血管抑素结构同源，我们以前的报道显示NK 4抑制HGF刺激诱导的血管内皮细胞增殖。本研究的目的是阐明HGF对MM细胞生长的贡献，以及研究NK 4治疗用途的可能性。体外研究表明，NK 4蛋白稳定MM细胞系的生长，并调节c-MET、ERK 1/2、STAT 3和AKT-1的活化。将含有NK 4 cDNA的重组腺病毒（AdCMV. NK 4）肌肉注射到携带源自产生HGF的MM细胞的肿瘤的lcr/scid小鼠中。NK 4能显著抑制肿瘤的生长。组织学检查显示AdCMV.NK4诱导MM细胞凋亡，伴随着肿瘤中新生血管的减少。因此，NK 4通过抗血管生成以及直接抗肿瘤机制抑制MM细胞的生长。NK 4分子靶向治疗肝细胞生长因子可能成为MM治疗的新途径。
Hepatocyte growth factor (HGF) promotes cell growth and motility and also increases neovascularization. Multiple myeloma (MM) cells produce HGF, and the plasma concentration of HGF is significantly elevated in patients with clinically active MM, suggesting that HGF might play a role in the pathogenesis of MM. NK4, an antagonist of HGF, is structurally homologous to angiostatin, and our previous report showed that NK4 inhibited the proliferation of vascular endothelial cells induced by HGF stimulation. The purposes of this study were to elucidate the contribution of HGF to the growth of MM cells as well as to investigate the possibility of the therapeutic use of NK4. In vitro study showed that NK4 protein stabilized the growth of MM cell lines and regulated the activation of c-MET, ERK1/2, STAT3, and AKT-1. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was injected intramuscularly into lcr/scid mice bearing tumors derived from HGF-producing MM cells. AdCMV.NK4 significantly inhibited the growth of these tumors in vivo. Histologic examination revealed that AdCMV.NK4 induced apoptosis of MM cells, accompanied by a reduction in neovascularization in the tumors. Thus, NK4 inhibited the growth of MM cells via antiangiogenic as well as direct antitumor mechanisms. The molecular targeting of HGF by NK4 could be applied as a novel therapeutic approach to MM.