Leslie Michael C, Bar-Eli Menashe
Department of Cancer Biology, MD Anderson Cancer Center, Houston, Texas 77230-1429, USA.
J Cell Biochem. 2005 Jan 1;94(1):25-38. doi: 10.1002/jcb.20296.
The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not yet well defined. We have demonstrated that the progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18, MMP-2, the thrombin receptor (PAR-1), and lack of c-KIT expression. The transition from RGP to VGP is also associated with overexpression of the angiogenic factor IL-8. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of the transcription factors CREB and ATF-1, both of which may act as survival factors for human melanoma cells. Inactivation of CREB/ATF-1 activities in metastatic melanoma cells by dominant-negative CREB or by anti-ATF-1 single chain antibody fragment (ScFv), resulted in deregulation of MMP-2 and MCAM/MUC18, increased the sensitivity of melanoma cells to apoptosis, and inhibition of their tumorigenicity and metastatic potential in vivo. In this prospect article, we summarize our data on the role of AP-2 and CREB/ATF-1 in the progression of human melanoma and report on the development of new fully human antibodies anti-MCAM/MUC18 and anti-IL-8 which could serve as new modalities for the treatment of melanoma.
与黑色素瘤细胞从径向生长阶段（RGP）转变为垂直生长阶段（VGP，转移表型）相关的分子变化尚未完全明确。我们已经证明，人类黑色素瘤的进展与转录因子AP-2表达缺失有关。在转移性黑色素瘤细胞中，这种缺失导致MCAM/MUC18、MMP-2、凝血酶受体（PAR-1）的过表达，以及c-KIT表达的缺失。从RGP到VGP的转变还与血管生成因子IL-8的过表达有关。此外，黑色素瘤细胞从RGP到VGP的转变与转录因子CREB和ATF-1的过表达有关，这两者都可能作为人类黑色素瘤细胞的生存因子。通过显性负性CREB或抗ATF-1单链抗体片段（ScFv）使转移性黑色素瘤细胞中的CREB/ATF-1活性失活，导致MMP-2和MCAM/MUC18失调，增加黑色素瘤细胞对凋亡的敏感性，并抑制其在体内的致瘤性和转移潜能。在这篇前瞻性文章中，我们总结了关于AP-2和CREB/ATF-1在人类黑色素瘤进展中的作用的数据，并报告了新型全人源抗MCAM/MUC18和抗IL-8抗体的研发情况，这些抗体可作为治疗黑色素瘤的新方法。
