CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway
CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway
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DOI：
10.1016/j.bbrc.2007.05.182
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发表时间：
2007-08-03
影响因子：
3.1
通讯作者：
Shim, Hyunsuk
中科院分区：
文献类型：
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作者：
Liang, Zhongxing;Brooks, Joann;Shim, Hyunsuk
CXC 趋化因子受体 4 (CXCR4) 已被证明在趋化和归巢中发挥关键作用，这是癌症转移的关键步骤。也有越来越多的证据表明该受体与血管生成有关。然而，其分子基础仍然难以捉摸。血管内皮生长因子（VEGF）是主要的血管生成因子之一，促进渗漏肿瘤脉管系统的形成，这是肿瘤进展的标志。在这里，我们研究了 CXCR4 是否通过 PI3K/Akt 途径诱导 VEGF 的表达。我们的结果表明，CXCR4/CXCL12 诱导 Akt 磷酸化，从而导致 VEGF 在 mRNA 和蛋白质水平上上调。相反，阻断 Akt 信号传导的激活会导致 VEGF 蛋白水平下降；用 CXCR4 拮抗剂阻断 CXCR4/CXCL12 相互作用可抑制体内肿瘤血管生成和生长。此外，患者肿瘤样本中 VEGF mRNA 水平与 CXCR4 mRNA 水平密切相关。总之，我们的研究表明，CXCR4/CXCL12 信号轴可以通过激活 PI3K/Akt 通路增加 VEGF 的表达来诱导血管生成和肿瘤进展。我们的研究结果表明，靶向 CXCR4 可以提供一种潜在的新型抗血管生成疗法，以抑制原发性肿瘤和转移性肿瘤的形成。 (c) 2007 Elsevier Inc. 保留所有权利。
CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Our results showed that CXCR4/CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Our findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors. (c) 2007 Elsevier Inc. All rights reserved.