The Chemokine Receptor CXCR4 and the Metalloproteinase MT1-MMP Are Mutually Required during Melanoma Metastasis to Lungs
The Chemokine Receptor CXCR4 and the Metalloproteinase MT1-MMP Are Mutually Required during Melanoma Metastasis to Lungs
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DOI：
10.2353/ajpath.2009.080636
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发表时间：
2009-02-01
影响因子：
6
通讯作者：
Teixido, Joaquin
中科院分区：
文献类型：
--
作者：
Bartolome, Ruben A.;Ferreiro, Sergio;Teixido, Joaquin
黑色素瘤是最具侵袭性的皮肤癌，一旦转移开始；因此，表征参与黑色素瘤传播的分子参与者是很重要的。趋化因子受体CXCR4和膜结合金属蛋白酶MT1-MMP在黑色素瘤细胞上表达，是控制转移的候选分子。我们使用过表达或沉默CXCR4或MT1-MMP，或结合过表达和干扰这些蛋白的人类黑色素瘤转染物，发现CXCR4和MT1-MMP在黑色素瘤细胞转移到肺部的不同步骤中协调它们的活动。来自活体移植黑色素瘤小鼠肺定植模型、小鼠存活以及肺样本短期归巢式聚合酶链反应实验的结果表明，在黑色素瘤细胞到达肺部的早期阶段，CXCR4是必需的。相比之下，MT1-MMP并不需要这些初始步骤，而是通过CXCR4促进肿瘤的后续侵袭和传播。对CXCR4和MT1-MMP之间潜在串扰的研究表明，CXCR4配体CXCL12刺激黑色素瘤细胞后，MT1-MMP在细胞内积累，这一过程涉及Rac-Erk1/2通路的激活。在细胞与特定基底膜蛋白接触后，MT1-MMP以磷脂酰肌醇3-激酶依赖的方式重新分布到细胞膜上。这些结果表明，针对CXCR4和MT1-MMP的联合治疗应该改善目前治疗转移性黑色素瘤的局限性。（美国病理学杂志2009,174:602-612;DOI: 10.2353/ajpath.2009.080636）
Melanoma is the most aggressive skin cancer once metastasis begins; therefore, it is important to characterize the molecular players involved in melanoma dissemination. The chemokine receptor CXCR4 and the membrane-bound metalloproteinase MT1-MMP are expressed on melanoma cells and represent candidate molecules for the control of metastasis. Using human melanoma transfectants that either overexpress or silence CXCR4 or MT1-MMP, or that have a combination of overexpression and interference of these proteins, we show that CXCR4 and MT1-MMP coordinate their activities at different steps along melanoma cell metastasis into the lungs. Results from in vivo xenograft mouse models of melanoma lung colonization and mice survival and short-term, homing nested polymerase chain reaction experiments from lung samples indicated that CXCR4 is required at early phases of melanoma cell arrival in the lungs. In contrast, MT1-MMP is not needed for these initial steps but promotes subsequent invasion and dissemination of the tumor with CXCR4. Investigation of potential cross talk between CXCR4 and MT1-MMP revealed that MT1-MMP accumulates intracellularly after melanoma cell stimulation with the CXCR4 ligand CXCL12, and that this process involves the activation of the Rac-Erk1/2 pathway. Subsequent to cell contact with specific basement membrane proteins, MT1-MMP redistributes to the cell membrane in a phosphatidylinositol 3-kinase-dependent manner. These results suggest that combination therapies that target CXCR4 and MT1-MMP should improve the limitations of the current therapies for metastatic melanoma. (Am J Pathol 2009, 174:602-612; DOI: 10.2353/ajpath.2009.080636)