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. Cancer Gene Therapy (2005) 12, 954-962.

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Most of them clearly show antineoplastic effects on various tumor cell types in vitro and in vivo such as decreased proliferation, migration and metastasis potential. Some of these experimental approaches such as adenoviral-mediated NK4 expression (Heideman et al, 2005) and antisense techniques have been successfully applied on HCC cells.…”

Abl interconnects oncogenic Met and p53 core pathways in cancer cells

“…We found that tumor growth caused by subcutaneous injection of HepG2 shAbl cells was significantly reduced compared with that induced by HepG2 control cells (Figures 2b and c), which tumorigenesis has been demonstrated to be dependent on Met. 25 Similarly, we observed that c-Abl antagonists restrained Met-triggered tumor growth in vivo by following mice injected intraperitoneally with GTL-16 cells engineered for in vivo non-invasive bioluminescence imaging (Figure 2d). Imatinib treatment led to a reduction of tumor weight by 49%, and of nodule number by 64% (sizeo2 mm) and 61% (size42 mm) (Figures 2e and f).…”

Antisense oligonucleotides targeting midkine inhibit tumor growth in an in situ human hepatocellular carcinoma model

“…In particular, the insulin-like growth factor/IGF-1 receptor (IGF/IGF-1R), hepatocyte growth factor (HGF) [8] , Wnt [9] , transforming growth factor alpha/epidermal growth factor receptor (TGF-α/EGFR) [10] , and TGF-β/TGF-βR [11,12] pathways contribute to proliferation, anti-apoptosis, and invasive behavior of tumor cells. Midkine (MK) was first identified in embryonic carcinoma cells in early stages during retinoic acid-induced differentiation [13] .…”