Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis.
Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis.
复制标题
剖析CCR2-CCL2轴在肿瘤存活和血管生成中的自分泌和旁分泌作用。
DOI：
10.1371/journal.pone.0028305
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Karin N
中科院分区：
文献类型：
--
作者：
Izhak L;Wildbaum G;Jung S;Stein A;Shaked Y;Karin N
CCL 2-CCR 2轴可能通过两种主要机制促进癌症疾病的发展和进展：CCL 2作为CCR 2+癌细胞的存活/生长因子的自分泌效应，以及CCR 2 + CX 3CR 1+肿瘤相关巨噬细胞的吸引力，其在不存在CCR 2的情况下几乎不迁移。到目前为止，还没有建立体内系统来区分这些特征中的每一个对癌症发展的选择性贡献。在这里，我们采用了一种嵌合体动物模型，其中所有的非恶性细胞都是CCR 2-/-，但所有的癌细胞都是CCR 2+，结合骨髓（BM）CX 3 CR 1+细胞的过继转移系统，这些细胞来自CCR 2+小鼠，携带增强型绿色荧光蛋白（EGFP）报告基因（cx 3 cr 1 gfp）靶向替换CX 3 CR 1基因，以及CD 45. 1同源基因。使用该系统，我们剖析了CX 3CR 1 + CCR 2+细胞（仅占CD 11b + BM细胞的约7%）对肿瘤发展和血管生成的选择性贡献。这表明除了它们的直接促血管生成作用外，它们对于将其他CD 11b+细胞募集到肿瘤部位是必不可少的。我们进一步表明，CCR 2-IG，选择性和特异性地中和CCL 2，给小鼠，其中CCR 2只在肿瘤细胞上表达，进一步抑制肿瘤的发展，暗示了这种趋化因子的关键作用，支持肿瘤的生存自分泌的方式。这进一步强调了CCL 2作为癌症疾病治疗靶标的重要作用。
The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX3CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2−/−, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX3CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX3CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx3cr1 gfp), together with the CD45.1 congene. Using this system we dissected the selective contribution of CX3CR1+CCR2+ cells, which comprise only about 7% of CD11b+ BM cells, to tumor development and angiogenesis. Showing that aside for their direct pro-angiogenic effect they are essential for the recruitment of other CD11b+ cells to the tumor site. We further show that the administration of CCR2-Ig, that selectively and specifically neutralize CCL2, to mice in which CCR2 is expressed only on tumor cells, further suppressed tumor development, implicating for the key role of this chemokine supporting tumor survival in an autocrine manner. This further emphasizes the important role of CCL2 as a target for therapy of cancer diseases.
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影响因子：
56.9
作者：
Asahara, T;Murohara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
8.8
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Hefler, L;Tempfer, C;Heinze, G;Mayerhofer, K;Breitenecker, G;Leodolter, S;Reinthaller, A;Kainz, C
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作者：
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Foerster, Reinhold
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作者：
Adams, JY;Johnson, M;Wu, L
通讯作者：
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