Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic antigen)
Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic antigen)
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DOI：
10.1158/0008-5472.can-05-0420
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Goldenberg, DM
中科院分区：
文献类型：
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作者：
Blumenthal, RD;Hansen, HJ;Goldenberg, DM
CEACAM5和CEACAM6在许多肿瘤中高表达，并与黏附和侵袭有关。针对这些抗原(CEACAM5和CEACAM6共有的NH2末端[MN-3]和A1B1结构域[MN-15]以及CEACAM5限制的A3B3结构域[MN-14])的三种不同表位的单抗在体外的迁移、侵袭和黏附实验中以及在GW-39人结肠微转移模型中进行了评估。MN-3Fab‘和MN-15Fab’均有抑制细胞迁移的作用。MN-15Fab‘处理抑制了侵袭，减少了细胞对细胞外基质(ECM)的穿透。在5种细胞系中，有4种细胞株的侵袭力也低于MN-15Fab‘，但MN-3Fab’也降低了侵袭。三种单抗均可使肿瘤细胞与血管内皮细胞的粘附率降低49%至58%。MN-15Fab‘而不是MN-3或MN-14 Fab’可诱导六种细胞系中的三种细胞对ECM蛋白、纤维连接蛋白的粘附力降低，但对玻璃体粘连蛋白、层粘连蛋白、I型胶原和IV型胶原的粘附力没有影响。体内研究表明，用MN-3Fab‘或MN-15Fab’治疗植入GW-39人结肠癌细胞的小鼠可提高其存活率(分别为P<；0.025和P<；0.01)。这些研究表明，针对CEACAM5或CEACAM6的抗体Fabs在体外影响细胞迁移、细胞侵袭和细胞黏附，而MN-15和MN-3 Fabs在体内具有抗转移作用，从而提高了转移小鼠的存活率。因此，阻断CEACAM5/CEACAM6的N和A1B1结构域可以阻止转移过程。
CEACAM5 and CEACAM6 are overexpressed in many cancers and are associated with adhesion and invasion. The effects of three monoclonal antibodies targeting different epitopes on these antigens (NH2-terminal [MN-3] and A1B1 domains [MN-15] shared by CEACAM5 and CEACAM6 and the A3B3 domain [MN-14] restricted to CEACAM5) were evaluated in migration, invasion, and adhesion assays in vitro using a panel of human pancreatic, breast, and colonic cancer cell lines, and in the GW-39 human colonic micrometastasis model in vivo. MN-3 Fab' and MN-15 Fab' were both effective at inhibiting cell migration. MN-15 Fab' treatment inhibited invasion, reducing cell penetration through an extracellular matrix (ECM). MN-3 Fab' also decreased invasion but was less effective than MN-15 Fab' in four of five cell lines. All three monoclonal antibody (mAb) Fabs decreased adhesion of tumor cells to endothelial cells by 49% to 58%. MN-15 Fab' but not MN-3 or MN-14 Fabs induced a decrease in adhesion of three of six cell lines to the ECM protein, fibronectin, but adhesion to vitronectin, laminin, collagen-I, and collagen-IV was not affected. In vivo studies showed that treatment with MN-3 Fab' or MN-15 Fab' of mice implanted with GW-39 human colonic cancer cells increased their survival (P < 0.025 and P < 0.01, respectively). These studies show that antibody Fabs that target either CEACAM5 or CEACAM6 affect cell migration, cell invasion, and cell adhesion in vitro, and that MN-15 and MN-3 Fabs have antimetastatic effects in vivo, resulting in improved survival of mice with metastases. Thus, blocking the N and A1B1 domains of CEACAM5/CEACAM6 can impede the metastatic process.