Effective angiostatic treatment in a murine metastatic and orthotopic hepatoma model

Hepatology. 2005 Jun;41(6):1233-40. doi: 10.1002/hep.20724.


Vascular endothelial growth factor (VEGF) activity is correlated with a progressive tumor disease in patients with hepatocellular carcinoma (HCC). In spite of the well-recognized role of VEGF in HCC, there are few data available regarding therapeutic strategies to block VEGF activity. Therefore, we employed a recombinant adenoviral vector encoding a soluble dominant negative fragment of VEGF receptor 2 (Flk-1), AdsFlk-1, to control pre-established murine orthotopic and metastatic hepatomas. Vector function was confirmed via reverse-transcriptase polymerase chain reaction and ELISA, and angiostatic effects were analyzed in vitro and in vivo. Antitumoral effects of systemic AdsFlk-1 application were studied in a subcutaneous and orthotopic Hepa129 HCC model. Cell supernatant containing the truncated form of Flk-1 had no direct effect on cell proliferation of Hepa129 cells in vitro but reduced endothelial tube formation on matrigel matrix by approximately 80% in vitro. Endothelial-like cell infiltration into matrigel plugs in vivo was also decreased by 80%. Systemic treatment of tumor-bearing mice inhibited tumor growth by 84% compared with the corresponding control group within 16 days after vector application. Likewise, the survival rate was significantly improved in the AdsFlk-1 group compared with control. Orthotopic tumor growth was reduced by 82%, and development of malignant ascites was also retarded. In conclusion, systemic adenoviral-mediated gene transfer of an Flk-1 fragment significantly inhibited tumor growth in orthotopic and metastatic murine HCC. The data support the value of VEGF blockade as an effective target for HCC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Bromodeoxyuridine
  • Carcinoma, Hepatocellular / blood supply*
  • Carcinoma, Hepatocellular / pathology
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Collagen
  • Drug Combinations
  • Female
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Vectors
  • Humans
  • Laminin
  • Liver Neoplasms / blood supply*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Microcirculation / drug effects
  • Neovascularization, Pathologic / pathology*
  • Peptide Fragments / genetics
  • Proteoglycans
  • Solubility
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2* / chemistry
  • Vascular Endothelial Growth Factor Receptor-2* / genetics
  • Vascular Endothelial Growth Factor Receptor-2* / metabolism


  • Angiogenesis Inhibitors
  • Drug Combinations
  • Laminin
  • Peptide Fragments
  • Proteoglycans
  • Vascular Endothelial Growth Factor A
  • matrigel
  • Collagen
  • Vascular Endothelial Growth Factor Receptor-2
  • Bromodeoxyuridine