Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells.
Hypoxia induced CCL28 promotes angiogenesis in lung adenocarcinoma by targeting CCR3 on endothelial cells.
复制标题
缺氧诱导的 CCL28 通过靶向内皮细胞上的 CCR3 促进肺腺癌的血管生成
DOI：
10.1038/srep27152
复制
发表时间：
2016-06-02
影响因子：
4.6
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Huang G;Tao L;Shen S;Chen L
肿瘤缺氧是肺腺癌的重要特征之一。趋化因子可能介导肿瘤缺氧的作用。在肿瘤组织和患者血清中证实，CC趋化因子28（CCL 28）是肺腺癌细胞中唯一的缺氧诱导的趋化因子。CCL 28可促进内皮细胞的管腔形成、迁移和增殖。此外，CCL 28在鸡胚绒毛尿囊膜和无胸腺裸鼠背部植入的基质胶中促进血管生成（CByJ. Cg-Foxn 1 nu/J）。CCL 28高表达的肺腺癌细胞形成的肿瘤生长更快，血管密度更高，而CCL 28表达敲低的肺腺癌细胞的肿瘤形成率非常低，血管密度更低。免疫组化结果显示，肺腺癌组织中血管内皮细胞高度表达CCL 28受体CCR 3。通过磷酸化抗体阵列分析了内皮细胞中由CCL 28调节的进一步信号传导途径。CCL 28/CCR 3信号通路在PI 3 K-Akt、p38 MAPK和PLC γ水平可绕过VEGF/VEGFR信号通路。这种作用可被抗CCR 3抗体中和。结论：CCL 28作为肿瘤乏氧诱导的趋化因子，可通过靶向微血管内皮细胞上的CCR 3促进肺腺癌血管生成。
Tumor hypoxia is one of the important features of lung adenocarcinoma. Chemokines might mediate the effects caused by tumor hypoxia. As confirmed in tumor tissue and serum of patients, CC chemokine 28 (CCL28) was the only hypoxia induced chemokine in lung adenocarcinoma cells. CCL28 could promote tube formation, migration and proliferation of endothelial cells. In addition, angiogenesis was promoted by CCL28 in the chick chorioallantoic membrane and matrigel implanted in dorsal back of athymic nude mice (CByJ.Cg-Foxn1nu/J). Tumors formed by lung adenocarcinoma cells with high expression of CCL28 grew faster and had a higher vascular density, whereas tumor formation rate of lung adenocarcinoma cells with CCL28 expression knockdown was quite low and had a lower vascular density. CCR3, receptor of CCL28, was highly expressed in vascular endothelial cells in lung adenocarcinoma when examining by immunohistochemistry. Further signaling pathways in endothelial cells, modulated by CCL28, were analyzed by Phosphorylation Antibody Array. CCL28/CCR3 signaling pathway could bypass that of VEGF/VEGFR on the levels of PI3K-Akt, p38 MAPK and PLC gamma. The effects could be neutralized by antibody against CCR3. In conclusion, CCL28, as a chemokine induced by tumor hypoxia, could promote angiogenesis in lung adenocarcinoma through targeting CCR3 on microvascular endothelial cells.