Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner
Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner
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DOI：
10.1158/0008-5472.can-04-3833
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发表时间：
2005-07-01
期刊：
影响因子：
11.2
通讯作者：
Omata, M
中科院分区：
文献类型：
--
作者：
Guleng, B;Tateishi, K;Omata, M
趋化因子受体CXCR4与其特异性配体基质细胞衍生因子-1(SDF-1/CXCL12)之间的相互作用介导了多种细胞功能。在癌症中，在肿瘤组织中检测到不同谱系的SDF-1阳性或CXCR4阳性细胞。最近深入的研究表明，阻断CXCR4可能会降低癌细胞的转移潜力。在这里，我们证明了SDF-1/CXCR4轴的抑制减少了S.C.的生长。胃肠道肿瘤通过抑制肿瘤新生血管生成。CXCR4中和对小鼠Colon38和PancO2细胞的体内生长有抑制作用，而对Colon3s和PancO2细胞的体外生长无影响。肿瘤生长的这种抑制被发现与癌细胞本身的CXCR4的表达无关，因为CXCR4被击倒的Colon38细胞与对照细胞生长相似。此外，阻断CXCR4后，CD31阳性的肿瘤毛细血管减少到45%(P<；0.001)，肿瘤内血流量减少到65%(P<；0.01)。CXCR4的中和不影响肿瘤组织中血管内皮生长因子(VEGF)的浓度。结合肿瘤组织中CXCR4阳性内皮细胞的检测，提示阻断CXCR4的抗血管生成作用与减少肿瘤内皮细胞的建立有关，而不依赖于对血管内皮生长因子的抑制。我们的数据表明，SDF-1/CXCR4通路可能是抗癌策略的一般靶点，阻断该系统可能与其他抗血管生成治疗(如阻断血管内皮生长因子)协同有效。
The interaction between the chemokine receptor CXCR4 and its specific ligand, stromal cell-derived factor-1 (SDF-1/CXCL12), mediates several cellular functions. In cancer, SDF-1-positive or CXCR4-positive cells of various lineages are detected within tumor tissues. Recent intensive research has indicated the possibility that blocking CXCR4 could reduce the metastatic potential of cancer cells. Here, we show that the inhibition of the SDF-1/CXCR4 axis decreases the growth of s.c. gastrointestinal tumors through the suppression of tumor neoangiogenesis. The neutralization of CXCR4 suppressed the growth in vivo of tumors derived from mouse Colon38 and PancO2 cells, whereas it did not affect the growth of Colon3s and PancO2 cells in vitro. This attenuation of tumor growth was found to be independent of the expression of CXCR4 by the cancer cells themselves, because CXCR4 knocked-down Colon38 cells grew similarly to control cells. Furthermore, CD31-positive tumor capillaries were reduced to 45% (P < 0.001) and intratumor blood flows were decreased to 65% (P < 0.01) by blockade of CXCR4. The vascular endothelial growth factor (VEGF) concentration in the tumors was not affected by the neutralization of CXCR4. Taken together with the detection of CXCR4-positive endothelial cells in the tumor tissues, the findings suggest that the antiangiogenic effects of the blockade of CXCR4 are related to a reduction of the establishment of tumor endothelium independently of VEGF inhibition. Our data indicate that the SDF-1/CXCR4 pathway might be a general target for anticancer strategies and that blocking this system could be cooperatively effective in combination with other antiangiogenic therapies, such as blockade of VEGF.