The kringle domain of tissue-type plasminogen activator inhibits in vivo tumor growth.
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.
Shim
Byoung-Shik
BS
Cancer Research Institute, Catholic Research Institutes of Medical Sciences, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
Kang
Byoung-Hak
BH
Hong
Yong-Kil
YK
Kim
Hyun-Kyung
HK
Lee
Il-Ha
IH
Lee
Soo-Young
SY
Lee
Young-Joon
YJ
Lee
Suk-Keun
SK
Joe
Young Ae
YA
D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018082:Kringles; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D010959:Tissue Plasminogen Activator / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D042501:Angiogenic Proteins; D005337:Fibrin; D010959:Tissue Plasminogen Activator