Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs
Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs
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DOI：
10.1074/jbc.m109.083550
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发表时间：
2010-04-02
影响因子：
4.8
通讯作者：
Mukherjee, Anil B.
中科院分区：
文献类型：
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作者：
Saha, Arjun;Lee, Yi-Ching;Mukherjee, Anil B.
新出现的证据表明炎症与癌症转移之间存在联系，但分子机制尚不清楚。子宫红蛋白（UG）是一种有效的抗炎蛋白，在几乎所有哺乳动物的肺中都有组成性表达。ug敲除（UG-KO）小鼠易患肺部炎症，B16F10黑色素瘤细胞优先转移到肺部，提供了模型系统的组成部分，以确定炎症和转移是如何联系在一起的。我们在这里报道，将B16F10细胞注射到UG-KO小鼠的尾静脉中，与野生型幼崽相比，在肺部形成的肿瘤菌落数量明显增加。值得注意的是，UG-KO小鼠肺过表达两种钙结合蛋白S100A8和S100A9，而B16F10细胞表达晚期糖基化终产物受体（RAGE），这是这些蛋白的已知受体。此外，S100A8和S100A9对表达RAGE的B16F10细胞是有效的化学引诱剂，用RAGE阻断抗体预处理这些细胞可抑制迁移和侵袭。有趣的是，在UG-KO小鼠中，血液中的S100A8/S100A9浓度在尾静脉中最低，在肺部最高，这很可能引导B16F10细胞迁移到肺部。此外，用S100A8或S100A9处理的B16F10细胞过表达基质金属蛋白酶，已知其促进肿瘤侵袭。最值得注意的是，UG-KO小鼠肺中转移的B16F10细胞表达MMP-2， MMP-9和MMP-14以及furin，一种激活MMPs的前蛋白转化酶。综上所述，我们的研究结果表明，缺乏抗炎蛋白会导致黑色素瘤细胞的肺部定植增加，并将RAGE确定为潜在的抗转移药物靶点。
Emerging evidence indicates a link between inflammation and cancer metastasis, but the molecular mechanism(s) remains unclear. Uteroglobin (UG), a potent anti-inflammatory protein, is constitutively expressed in the lungs of virtually all mammals. UG-knock-out (UG-KO) mice, which are susceptible to pulmonary inflammation, and B16F10 melanoma cells, which preferentially metastasize to the lungs, provide the components of a model system to determine how inflammation and metastasis are linked. We report here that B16F10 cells, injected into the tail vein of UG-KO mice, form markedly elevated numbers of tumor colonies in the lungs compared with their wild type littermates. Remarkably, UG-KO mouse lungs overexpress two calcium-binding proteins, S100A8 and S100A9, whereas B16F10 cells express the receptor for advanced glycation end products (RAGE), which is a known receptor for these proteins. Moreover, S100A8 and S100A9 are potent chemoattractants for RAGE-expressing B16F10 cells, and pretreatment of these cells with a blocking antibody to RAGE suppressed migration and invasion. Interestingly, in UG-KO mice S100A8/S100A9 concentrations in blood are lowest in tail vein and highest in the lungs, which most likely guide B16F10 cells to migrate to the lungs. Further, B16F10 cells treated with S100A8 or S100A9 overexpress matrix metalloproteinases, which are known to promote tumor invasion. Most notably, the metastasized B16F10 cells in UG-KO mouse lungs express MMP-2, MMP-9, and MMP-14 as well as furin, a pro-protein convertase that activates MMPs. Taken together, our results suggest that a lack of an anti-inflammatory protein leads to increased pulmonary colonization of melanoma cells and identify RAGE as a potential anti-metastatic drug target.