Heideman Daniëlle A M, Overmeer Renée M, van Beusechem Victor W, Lamers Wouter H, Hakvoort Theodorus B M, Snijders Peter J F, Craanen Mikael E, Offerhaus G Johan A, Meijer Chris J L M, Gerritsen Winald R
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Cancer Gene Ther. 2005 Dec;12(12):954-62. doi: 10.1038/sj.cgt.7700856.
NK4 is an hepatocyte growth factor (HGF)-antagonist and a broad angiogenesis inhibitor. NK4 gene therapy has confirmed antitumor efficacy on cancers with intact HGF-cMET signaling pathway. However, the feasibility to treat tumors in which the effect of the HGF-cMET signaling pathway is less unambiguous or may even be inhibitory on carcinogenesis, such as hepatocellular carcinoma (HCC) with NK4 needs further assessment. Therefore, we evaluated the effects of adenoviral vector-mediated expression of NK4 on the biological behavior of a series of HCC cell lines in vitro and on HepG2 xenografts in vivo. In vitro, transduction of HCC cell lines with the replication-deficient recombinant adenoviral vector AdCMV.NK4 resulted in significant inhibition of proliferation over and above the antimitogenic effects of HGF. In addition, HGF-induced scattering and invasion through matrigel were inhibited effectively. Moreover, transduced HCC cells produced sufficient amounts of NK4 protein to achieve bystander effects involving reduced migration of nontransduced tumor cells and reduced proliferation of endothelial cells. Finally, treatment of established HepG2 xenografts with AdCMV.NK4 resulted in significant tumor growth delay and significant reduction of intratumoral microvessel density. In conclusion, NK4 gene therapy is a promising strategy to treat HCC based on the pleiotropic functions of NK4 interfering with tumor growth, invasion, metastasis and angiogenesis.
NK4是一种肝细胞生长因子（HGF）拮抗剂和广泛的血管生成抑制剂。NK4基因治疗已证实对具有完整HGF-cMET信号通路的癌症具有抗肿瘤疗效。然而，对于HGF-cMET信号通路的作用不太明确甚至可能对致癌作用有抑制作用的肿瘤，如肝细胞癌（HCC），用NK4进行治疗的可行性需要进一步评估。因此，我们评估了腺病毒载体介导的NK4表达对一系列HCC细胞系体外生物学行为以及对体内HepG2异种移植瘤的影响。在体外，用复制缺陷型重组腺病毒载体AdCMV.NK4转导HCC细胞系，除了HGF的抗有丝分裂作用外，还导致增殖受到显著抑制。此外，HGF诱导的通过基质胶的散射和侵袭也被有效抑制。而且，转导的HCC细胞产生了足够量的NK4蛋白，以实现旁观者效应，包括未转导肿瘤细胞迁移减少和内皮细胞增殖减少。最后，用AdCMV.NK4治疗已建立的HepG2异种移植瘤导致肿瘤生长显著延迟和肿瘤内微血管密度显著降低。总之，基于NK4干扰肿瘤生长、侵袭、转移和血管生成的多效性功能，NK4基因治疗是一种有前景的治疗HCC的策略。
