Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma.
Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma.
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发表时间：
2002-09
期刊：
影响因子：
11.2
通讯作者：
L. Mills;C. Tellez;Suyun Huang;C. Baker;M. McCarty;L. Green;J. Gudas;Xiao Feng;M. Bar‐eli
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文献类型：
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作者：
L. Mills;C. Tellez;Suyun Huang;C. Baker;M. McCarty;L. Green;J. Gudas;Xiao Feng;M. Bar‐eli
MCAM/MUC 18表达与裸鼠人黑素瘤细胞的肿瘤厚度和转移潜能相关。此外，MUC 18在原发性皮肤黑色素瘤细胞中的异位表达导致体内肿瘤生长和转移增加。在这里，我们测试了全人抗MUC 18抗体ABX-MA 1对血管生成、肿瘤生长和转移的影响。ABX-MA 1对体外培养的黑色素瘤细胞增殖率无影响。然而，当将转移性黑色素瘤细胞系A375 SM和WM 2664（其表达高水平的MUC 18）的细胞s.c.移植到裸鼠中并用ABX-MA 1（100 μ g，每周，腹膜内，持续5周）处理，与对照IgG处理的小鼠相比，肿瘤生长被显著抑制。ABX-MA 1治疗也抑制了这些黑色素瘤细胞的实验性肺转移。ABX-MA 1在体外破坏表达MUC 18的黑素瘤细胞的球状体形成（同型相互作用）以及这些细胞附着于人血管内皮细胞[HUVEC（MUC 18阳性）]的能力。ABX-MA 1处理黑色素瘤细胞在体外显着抑制基质金属蛋白酶2的启动子和胶原酶活性，导致通过Matrigel涂层过滤器的侵袭减少。基质金属蛋白酶2的表达也在体内植入肿瘤中观察到降低。此外，由于HUVEC也表达MUC 18，ABX-MA 1在体外血管形成测定中直接破坏HUVEC的管样形成。总的来说，这些结果表明ABX-MA 1作为单独或与常规化疗或其他抗肿瘤剂组合治疗黑素瘤的方式是有用的。
MCAM/MUC18 expression correlates with tumor thickness and metastatic potential of human melanoma cells in nude mice. Moreover, ectopic expression of MUC18 in primary cutaneous melanoma cells leads to increased tumor growth and metastasis in vivo. Here we tested the effect of a fully human anti-MUC18 antibody, ABX-MA1, on angiogenesis, tumor growth, and metastasis. ABX-MA1 had no effect on melanoma cell proliferation rate in vitro. However, when cells of the metastatic melanoma lines A375SM and WM2664 (which express high levels of MUC18) were injected s.c. into nude mice and treated with ABX-MA1 (100 micro g, weekly, i.p. for 5 weeks), tumor growth was significantly inhibited compared with control IgG-treated mice. ABX-MA1 treatment also suppressed experimental lung metastasis of these melanoma cells. ABX-MA1 disrupted spheroid formation by melanoma cells expressing MUC18 (homotypic interaction) and the ability of these cells to attach to human vascular endothelial cells [HUVECs (MUC18 positive)] in vitro. ABX-MA1 treatment of melanoma cells in vitro significantly inhibited the promoter and collagenase activity of matrix metalloproteinase 2, resulting in decreased invasion through Matrigel-coated filters. Decreased expression of matrix metalloproteinase 2 was also observed in the implanted tumors in vivo. Moreover, because HUVECs also express MUC18, ABX-MA1 directly disrupted the tube-like formation by HUVECs in an in vitro vessel formation assay. Collectively, these results point to usefulness of ABX-MA1 as a modality to treat melanoma either alone or in combination with conventional chemotherapy or other antitumor agents.