Human tongue carcinoma growth is inhibited by selective antigelatinolytic peptides.
Matrix metalloproteinases (MMP-2 and MMP-9, or gelatinases) are involved in tongue SCC invasion, metastasis and angiogenesis. We have recently shown that a novel and selective hydrophobic cyclic CTTHWGFTLC (CTT1) peptide is inhibitor for MMP-2 and MMP-9 (Koivunen et al., Nat Biotechnol 1999; 17:768-74). In this study, we demonstrate that both the new hydrophilic derivate GRENYHGCTTHWGFTLC (CTT2) peptide and the CTT1 peptide inhibited specifically the human tongue squamous cell carcinoma (HSC-3) cell-derived gelatinolytic activity and in vitro invasion and migration of these cells (p < or = 0.049). In situ zymography revealed that both peptides also inhibited clearly almost all of the gelatinolytic activity present in the human tongue SCC tissue sections, indicating that MMP-2 and MMP-9 are the major gelatinases detected in the tongue carcinomas. However, CTT2 did not inhibit the type I collagen degradation by human collagenases (MMP-1, MMP-8 and MMP-13). Furthermore, CTT2 reduced the blood vessel density (p < or = 0.043) and clearly improved the survival of the mice bearing human tongue carcinoma xenografts (p < or = 0.012). Overall, we suggest that CTT1 and CTT2 peptides being selective gelatinase inhibitors with significant anti-tumor properties could be useful to diminish the invasion and angiogenesis of human tongue carcinomas characterized by enhanced gelatinolytic activity in tumors.
Heikkilä
Pia
P
Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Institute of Dentistry, University of Helsinki, Helsinki, Finland. pia.heikkila@helsinki.fi
Suojanen
Juho
J
Pirilä
Emma
E
Väänänen
Anu
A
Koivunen
Erkki
E
Sorsa
Timo
T
Salo
Tuula
T
D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology*; D049109:Cell Proliferation; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010456:Peptides, Cyclic / Q000502:physiology*; D014062:Tongue Neoplasms / Q000201:enzymology* / Q000473:pathology*; D014183:Transplantation, Heterologous
C415426:CTTHWGFTLC peptide; C509825:GRENYHGCTTHWGFTLC peptide; D061965:Matrix Metalloproteinase Inhibitors; D010456:Peptides, Cyclic; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9