The kringle domain of tissue-type plasminogen activator inhibits in vivo tumor growth

Biochem Biophys Res Commun. 2005 Feb 25;327(4):1155-62. doi: 10.1016/j.bbrc.2004.12.126.

Abstract

The two-kringle domain of tissue-type plasminogen activator (t-PA) has previously been shown to contain anti-angiogenesis activity. In this study, we explored the potential in vivo anti-tumor effects of the recombinant kringle domain (TK1-2) of human t-PA. Anti-tumor effects of purified Pichia-driven TK1-2 were examined in nude mice models by subcutaneous implantation of human lung (A-549) and colon (DLD-1, HCT-116) cancer cell lines. Mice bearing the tumors were injected with PBS or purified TK1-2 (30 mg/kg) i.p. every day for 22 days. TK1-2 treatment suppressed the A-549, DLD-1, and HCT-116 tumor growth by 85.3%, 52.4%, and 62.5%, respectively. Immunohistological examination of the tumor tissues showed that TK1-2 treatment decreased the vessel density and also the expression of angiogenesis-related factors including angiogenin, VEGF, alpha-SMA, vWF, and TNF-alpha, and increased the apoptotic fraction of cells. TK1-2 neither inhibited in vitro growth of these cancer cells nor affected t-PA-mediated fibrin clot lysis. These results suggest that TK1-2 inhibits the tumor growth by suppression of angiogenesis without interfering with fibrinolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenic Proteins / metabolism
  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Fibrin / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Kringles*
  • Male
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / blood supply
  • Neoplasms / drug therapy*
  • Neoplasms / pathology*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tissue Plasminogen Activator / chemistry*
  • Tissue Plasminogen Activator / metabolism
  • Tissue Plasminogen Activator / pharmacology*
  • Tissue Plasminogen Activator / therapeutic use

Substances

  • Angiogenic Proteins
  • Fibrin
  • Tissue Plasminogen Activator