title: Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy.
abstract: 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.
authors.affiliation: Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. dam.heideman@vumc.nl
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Renée M
authors.initials: RM
authors.lastname: Overmeer
authors.forename: Victor W
authors.initials: VW
authors.lastname: van Beusechem
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.forename: Theodorus B M
authors.initials: TB
authors.lastname: Hakvoort
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Mikael E
authors.initials: ME
authors.lastname: Craanen
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met