Human tongue carcinoma growth is inhibited by selective antigelatinolytic peptides

Abstract

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 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 0.043) and clearly improved the survival of the mice bearing human tongue carcinoma xenografts (p 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. ' 2005 Wiley-Liss, Inc.Key words: tongue carcinoma; matrix metalloproteinase; small peptide inhibitors; invasion Worldwide, oral and pharynx cancer is the eighth most common solid tumor, representing about 5% of all the malignancies.1 The incidence of oral cancer, especially mobile tongue carcinoma, is increasing, representing over one third of the malignant tumors in the oral cavity. Overall mortality rate has been unchanged over the last decades and over 50% of tongue SCC patients die within 5 years. Especially in advanced tumors, surgery and radiation therapy are often insufficient for the clinical management of tongue cancer patients, and metastases are frequently the cause for the death. 2-4

A novel and selective membrane type-1 matrix metalloproteinase (MT1-MMP) inhibitor reduces cancer cell motility and tumor growth

“…23 Similar results have been demonstrated for the antigelatinolytic CTT peptide. 11 Although in some reports MT1-MMP has also been linked to induced tumour neoangiogenesis, partially through proMMP-2 activation, 24,25 here the inhibition of MT1-MMP activation did not affect vasculature growth in carcinoma xenografts.…”

“…In this regard, peptides such as CTT1, CTT2 and the here reported PG are selective and effective MMP inhibitors. 10,11 They effectively reduce oral SCC invasion potential in vitro and tumor progression in vivo. In the future, specific antiproteolytic peptides may have a role as anticancer therapeutics especially if MMP profiles of each tumor are evaluated individually.…”

“…[10][11][12] We have also further showed that these antigelatinolytic peptides (CTT1 and CTT2) exert potential to inhibit gelatinase-dependent cancer cell migration and invasion in vitro as well as tumor growth and angiogenesis in vivo. 11 Nonetheless, CTTs do not inhibit another important cancer-associated MMP, the membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14).…”

“…Substrate proteolysis was characterized by SDS-PAGE (for β-casein) or western blotting (for Ln-332) as described elsewhere. 11,19 Cells were cultured in serum free medium with peptide G or controls for 48 h and MMP production and activity in culture media was detected by western-immunoblotting and gelatin zymography as described elsewhere. 11,19 In vitro cell invasion and migration.…”

“…11,19 Cells were cultured in serum free medium with peptide G or controls for 48 h and MMP production and activity in culture media was detected by western-immunoblotting and gelatin zymography as described elsewhere. 11,19 In vitro cell invasion and migration. Cell invasion and migration potential was studied using 8.0 μm pore size Matrigel TM invasion chambers and control inserts of equal size (BD Biosciences, MA, USA).…”