Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer
Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer
复制标题
DOI：
10.4049/jimmunol.172.5.2853
复制
发表时间：
2004-03-01
影响因子：
4.4
通讯作者：
Strieter, RM
中科院分区：
文献类型：
--
作者：
Keane, MP;Belperio, JA;Strieter, RM
Glu-Leu-Arg（+）（ELR+）CXC趋化因子是有效的血管生成促进剂，并且已被证明诱导显著部分的非小细胞肺癌衍生的血管生成活性并支持肿瘤发生。ELR+ CXC趋化因子共享共同的趋化因子受体CXCR 2。我们假设CXCR 2介导ELR+ CXC趋化因子在肿瘤发生过程中的促血管生成作用。为了检验这一假设，我们在C57 BL/6小鼠中使用了同基因鼠刘易斯肺癌（LLC; 3LL，H-2（B））异位和原位肿瘤模型系统，所述小鼠是CXCR 2（+/+）和CXCR 2（-/-）的充满和缺乏。我们首先证明了内源性ELR+ CXC趋化因子的表达与LLC肿瘤的肿瘤生长和转移潜力的相关性。接下来，我们发现LLC原发性肿瘤在CXCR 2（-/-）小鼠中的生长显著减少。此外，我们发现CXCR 2（-/-）小鼠的异位肿瘤自发转移到肺的显著减少。CXCR 2（-/-）小鼠原发性肿瘤的形态学分析显示坏死增加和血管密度降低。使用CXCR 2特异性中和抗体在CXCR 2（+/+）小鼠中进一步证实了这些发现。这些研究的结果支持CXCR 2介导肺癌临床前模型中ELR+ CXC趋化因子的血管生成活性的观点。
The Glu-Leu-Arg(+) (ELR+) CXC chemokines are potent promoters of angiogenesis and have been demonstrated to induce a significant portion of nonsmall cell lung cancer-derived angiogenic activity and support tumorigenesis. ELR+ CXC chemokines share a common chemokine receptor, CXCR2. We hypothesized that CXCR2 mediates the proangiogenic effects of ELR+ CXC chemokines during tumorigenesis. To test this postulate, we used syngeneic murine Lewis lung cancer (LLC; 3LL, H-2(b)) heterotopic and orthotopic tumor model systems in C57BL/6 mice replete (CXCR2(+/+)) and deficient in CXCR2 (CXCR2(-/-)). We first demonstrated a correlation of the expression of endogenous ELR+ CXC chemokines with tumor growth and metastatic potential of LLC tumors. Next, we found that LLC primary tumors were significantly reduced in growth in CXCR2(-/-) mice. Moreover, we found a marked reduction in the spontaneous metastases of heterotopic tumors to the lungs of CXCR2(-/-) mice. Morphometric analysis of the primary tumors in CXCR2(-/-) mice demonstrated increased necrosis and reduced vascular density. These findings were further confirmed in CXCR2(+/+) mice using specific neutralizing,Abs to CXCR2. The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR+ CXC chemokines in a preclinical model of lung cancer.