A new pseudo-peptide of Arg-Gly-Asp (RGD) inhibits intrahepatic metastasis of orthotopically implanted murine hepatocellular carcinoma.
A new pseudo-peptide of Arg-Gly-Asp (RGD) inhibits intrahepatic metastasis of orthotopically implanted murine hepatocellular carcinoma.
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DOI：
10.3892/ijo.20.2.319
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发表时间：
2002-02
影响因子：
5.2
通讯作者：
Yasunori Tsuchiya;S. Sawada;K. Tsukada;I. Saiki
中科院分区：
文献类型：
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作者：
Yasunori Tsuchiya;S. Sawada;K. Tsukada;I. Saiki
我们之前报道了基质金属蛋白酶-9 （MMP-9）、膜型1型基质金属蛋白酶（MT1-MMP）和β 1整合素在小鼠肝细胞癌（HCC）中的表达与肝内转移的发生有关，这被认为是复发的主要方式。本研究表明，静脉注射人工合成RGD伪肽（FC-336）可抑制小鼠肝细胞癌（CBO140C12）肿瘤碎片原位植入产生的肝内转移（p<0.05），但不影响植入肿瘤的生长。为了进一步分析FC-336的抗转移作用，我们在体外研究了FC-336对肿瘤生长、粘附和侵袭的影响。FC-336在无细胞毒浓度< 5 mg/ml时，能有效抑制CBO140C12细胞的粘附和侵袭（p<0.05）。我们还使用酶谱法检测了FC-336对CBO140C12细胞产生的MMPs明胶溶解的影响。FC-336以浓度依赖的方式抑制MMP-9对明胶底物的降解。这些结果强烈提示，CBO140C12肿瘤的肝内转移部分是由于肿瘤细胞在肿瘤表面分别表达MMP-9和整合素alpha3beta1 （vla3）、整合素alpha5beta1 （vla5）介导的侵袭和粘附能力显著。
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.