CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer
CXC-chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer
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DOI：
10.1002/ijc.24383
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发表时间：
2009-09-01
影响因子：
6.4
通讯作者：
Guha, Sushovan
中科院分区：
文献类型：
--
作者：
Matsuo, Yoichi;Raimondo, Massimo;Guha, Sushovan
血管生成是肿瘤生长和转移的必要条件。虽然ELR+- cxc趋化因子及其相应的受体cxc受体2 （CXCR2）是已知的血管生成介质，但对其在胰腺癌（PaCa）中的作用知之甚少。我们的研究目的是确定ELR+- cxc趋化因子/CXCR2生物轴在促进PaCa血管生成中的作用。我们前瞻性地收集了正常个体分泌素刺激的外分泌胰腺分泌物（SSEPS）；（NP）和PaCa患者。我们发现，PaCa患者SSEPS中ELR+- cxc趋化因子的总浓度显著高于NP患者（p = 0.002）。我们在多个PaCa细胞系的上清液中检测了ELR+- cxc趋化因子的水平，并证实BxPC-3、Colo-357和Panc-28的表达明显高于永生化人胰管上皮（HPDE）细胞系。在证实ELR+- cxc趋化因子对PaCa细胞缺乏自分泌作用（由于缺乏CXCR2表达）后，我们研究了这些趋化因子对人脐静脉内皮细胞（HUVEC）的旁分泌作用。重组ELR+- cxc趋化因子及与BxPC-3共培养均能显著增强HUVEC的增殖、侵袭和成管能力（p < 0.05）。这些生物学效应被CXCR2中和抗体（anti-CXCR2 Ab）显著抑制（p < 0.05）。最后，抗cxcr2 Ab可显著降低原位裸鼠PaCa模型的肿瘤体积（p < 0.05）、ki-67增殖指数（p = 0.043）和Factor VIII+微血管密度（p = 0.004）。我们的研究结果表明，ELR+- cxc趋化因子通过CXCR2促进PaCa肿瘤相关血管生成，提示CXCR2是PaCa的抗血管生成靶点。(c) 2009年
Angiogenesis is essential for tumor growth and metastasis. Although ELR+-CXC-chemokines and their corresponding receptor, CXC-receptor 2 (CXCR2), are known mediators of angiogenesis, little is known about their role in pancreatic cancer (PaCa). The aim of our study was to determine the role of ELR+-CXC-chemokine/CXCR2 biological axis in promoting PaCa angiogenesis. We prospectively collected secretin-stimulated exocrine pancreatic secretions (SSEPS) from normal individuals; (NP) and PaCa patients. We showed that summed concentrations of ELR+-CXC-chemokines in SSEPS from PaCa patients were significantly higher than in those from NP (p = 0.002). We measured ELR+-CXC-chemokine levels in supernatants from multiple PaCa cell lines and confirmed that BxPC-3, Colo-357 and Panc-28 had significantly higher expression compared with an immortalized human pancreatic ductal epithelial (HPDE) cell line. After confirming lack of autocrine effects of ELR+-CXC-chemokines on PaCa cells (due to absence of CXCR2 expression), we investigated paracrine effects of these chemokines on human umbilical vein endothelial cells (HUVEC). Both recombinant ELR+-CXC-chemokines and co-culturing with BxPC-3 significantly enhanced proliferation, invasion, and tube formation of HUVEC (p < 0.05). These biological effects were significantly inhibited by treatment with a neutralizing antibody against CXCR2 (anti-CXCR2 Ab) (p < 0.05). Finally, anti-CXCR2 Ab significantly reduced tumor volume (p < 0.05), ki-67 proliferation index (p = 0.043) and Factor VIII+ microvessel density (p = 0.004) in an orthotopic nude mouse PaCa model. Our results show that ELR+-CXC-chemokines promote PaCa tumor-associated angiogenesis through CXCR2, suggesting that CXCR2 is an anti-angiogenic target in PaCa. (C) 2009 UICC