Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells
Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells
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DOI：
10.1007/s12029-007-0011-7
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发表时间：
2006-12-01
影响因子：
1.6
通讯作者：
Urrutia, Raul
中科院分区：
文献类型：
--
作者：
Billadeau, Daniel D.;Chatterjee, Subrha;Urrutia, Raul
CXCL12及其受体CXCR4正成为调节几种人类癌症生长、血管生成和转移的有希望的靶点。事实上，阻断受体足以阻止实验性乳腺癌异种移植物的转移和血管生成。近年来，CXCR4在胰腺癌（最致命的肿瘤疾病之一）中的生物学作用已被报道。然而，CXCR4促进这些特性的分子机制尚不完全清楚。在本文中，我们描述了CXCR4在胰腺癌中激活的信号通路。我们发现在CXCR4激活后，EGFR发生酪氨酸磷酸化，并且该受体的激酶活性以及MMPs、Src和pi3激酶的激活是CXCR4介导的ERK激活所必需的。在胰腺癌细胞中对这一级联的分析表明，erk介导的通路调节了参与血管生成的基因，如VEGF、CD44、HIF1 α和IL-8。此外，ERK阻断抑制了CXCL12诱导的内皮细胞的迁移和成管。考虑到该通路中包括CXCR4本身在内的几种成分的抑制剂处于不同的临床试验阶段，本研究为这些药物在胰腺癌中的临床试验提供了理论依据，从而扩大了治疗这种令人沮丧的疾病的潜在靶点列表。
CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1 alpha, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.