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

• Published in: Biochemical and biophysical research communications 2005-02, Vol.327 (4), p.1155-1162
• Main Authors: Shim, Byoung-Shik, Kang, Byoung-Hak, Hong, Yong-Kil, Kim, Hyun-Kyung, Lee, Il-Ha, Lee, Soo-Young, Lee, Young-Joon, Lee, Suk-Keun, Joe, Young Ae
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenic Proteins - metabolism; Animals; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Fibrin - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Inhibitor; Kringle; 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; Tissue-type plasminogen activator; Tumor
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2004.12.126

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, α-SMA, vWF, and TNF-α, 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.