A new pseudo-peptide of Arg-Gly-Asp (RGD) inhibits intrahepatic metastasis of orthotopically implanted murine hepatocellular carcinoma.
We have previously reported that the expression of matrix metalloproteinase-9 (MMP-9), membrane type-1 matrix metalloproteinase (MT1-MMP) and beta1 integrins in murine hepatocellular carcinoma (HCC) was associated with the occurrence of intrahepatic metastasis, which is considered to be a major modality in recurrence. Here we show that intravenous administration of synthetic RGD pseudo-peptide (FC-336) inhibited intrahepatic metastasis produced by orthotopic implantation of a fragment of murine HCC (CBO140C12) tumor as compared with control administration of vehicle (p<0.05), but did not affect the growth of the implanted tumor. To further analyze the anti-metastatic effect of FC-336, we investigated the effects of FC-336 on tumor growth, adhesion and invasion in vitro. FC-336 at non-cytotoxic concentration of less than 5 mg/ml effectively inhibited the adhesion and invasion of CBO140C12 cells (p<0.05). We also used zymography to examine the effect of FC-336 on the gelatinolysis of MMPs produced by CBO140C12 cells. FC-336 inhibited the degradation of the gelatin substrate by MMP-9 in a concentration-dependent manner. These results strongly suggest that intrahepatic metastasis of CBO140C12 tumors is partly due to the marked invasive and adhesive abilities of tumor cells mediated by expression of MMP-9 and integrin alpha3beta1 (VLA-3), integrin alpha5beta1 (VLA-5) on the tumor surface, respectively.
Tsuchiya
Yasunori
Y
Second Department of Surgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.
Sawada
Shigeaki
S
Tsukada
Kazuhiro
K
Saiki
Ikuo
I
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000627:therapeutic use* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D020782:Matrix Metalloproteinases