Opposing roles of murine Duffy antigen receptor for chemokine and murine CXC chemokine receptor-2 receptors in murine melanoma tumor growth
Opposing roles of murine Duffy antigen receptor for chemokine and murine CXC chemokine receptor-2 receptors in murine melanoma tumor growth
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DOI：
10.1158/0008-5472.can-07-0246
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Richmond, Ann
中科院分区：
文献类型：
--
作者：
Horton, Linda W.;Yu, Yingchun;Richmond, Ann
趋化因子Duffy抗原受体（DARC）被归类为“沉默”受体，因为它可以结合CXC和CC趋化因子进行配体诱导的受体内化，但不与经典G蛋白偶联受体介导的信号传导所需的三聚体G蛋白偶联。CXC趋化因子受体-2 （CXCR2）已被证明在肿瘤血管生成中发挥重要作用。为了验证这两种趋化因子受体可能在黑色素瘤肿瘤生长中发挥相反作用的假设，我们开发了一种转基因小鼠模型，其中使用内皮素前原启动子/增强子（PPEP）驱动内皮细胞中DARC （mDARC）或CXCR2 （mCXCR2）的表达。我们在此表明，与对照小鼠相比，PPEP-mDARC和PPEP-mCXCR2转基因小鼠分别通过sc注射表达巨噬细胞炎症蛋白-2的永生化小鼠黑色素细胞建立的黑色素瘤异种移植物的生长受到抑制或增强。与对照组或mCXCR2转基因小鼠相比，mDARC转基因小鼠形成的早期肿瘤中浸润的白细胞数量明显增加，这表明内皮细胞上表达的DARC可能在白细胞迁移中起作用。此外，与对照组相比，mDARC转基因小鼠的肿瘤相关血管生成减少。相反，mCXCR2转基因小鼠的肿瘤血管生成明显增加。结果表明，内皮细胞过表达mDA-RC增加了白细胞向肿瘤的运输，减少了进入肿瘤的血管的生长，降低了肿瘤的生长速度，而内皮细胞过表达mCXCR2对肿瘤的血管生成和生长具有相反的作用。
The Duffy antigen receptor for chemokines (DARC) has been classified as a "silent" receptor, as it can bind CXC and CC chemokines to undergo ligand-induced receptor internalization, but is not coupled to trimeric G proteins required for the classic G protein-coupled receptor-mediated signaling. CXC chemokine receptor-2 (CXCR2) has been shown to play a major role in tumor angiogenesis. To test the hypothesis that these two chemokine receptors might play opposing roles in the growth of melanoma tumors, we developed a transgenic mouse model, where the preproendothelin promoter/enhancer (PPEP) is used to drive expression of either murine DARC (mDARC) or murine CXCR2 (mCXCR2) in endothelial cells. We show herein that the growth of melanoma tumor xenografts, established from s.c. injection of immortalized murine melanocytes overexpressing macrophage inflammatory protein-2, was inhibited or enhanced in the PPEP-mDARC and PPEP-mCXCR2 transgenic mice, respectively, compared with control mice. The early tumors formed in mDARC transgenic mice exhibited a significantly higher number of infiltrating leukocytes compared with either the control or mCXCR2 transgenic mice, suggesting a potential role for DARC expressed on endothelial cells in leukocyte migration. In addition, the tumor-associated angiogenesis in mDARC transgenic mice was reduced when compared with the control. Conversely, tumor angiogenesis was significantly increased in mCXCR2 transgenic mice. Results indicate that endothelial cell overexpression of mDA-RC increased leukocyte trafficking to the tumor, reduced the growth of blood vessels into the tumor, and reduced the growth rate of the tumor, whereas endothelial cell overexpression of mCXCR2 had the reverse effect on tumor angiogenesis and growth.