Human head and neck squamous cell carcinoma cells are both targets and effectors for the angiogenic cytokine, VEGF.
Human head and neck squamous cell carcinoma cells are both targets and effectors for the angiogenic cytokine, VEGF.
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DOI：
10.1002/jcb.21920
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发表时间：
2008-12-01
影响因子：
4
通讯作者：
Mallery, Susan R.
中科院分区：
文献类型：
--
作者：
Tong, Meng;Lloyd, Brandon;Pei, Ping;Mallery, Susan R.
以前的血管内皮生长因子 (VEGF) - 头颈鳞状细胞癌 (HNSCC) 研究重点关注 VEGF 对肿瘤相关血管生成的贡献。此前，我们已经证明 HNSCC 细胞产生高水平的 VEGF。因此，我们假设 VEGF 在 HNSCC 发病机制中发挥双相作用，即促血管生成和促肿瘤生成。蛋白质印迹证实培养的 HNSCC 细胞中存在 VEGF 的主要促有丝分裂受体 VEGFR-2/KDR 和 VEGFR-1/Flt-1。随后的研究评估了 VEGF 对 HNSCC 细胞内信号传导、有丝分裂、侵袭能力和基质金属蛋白酶 (MMP) 活性的影响。 hrVEGF165 的引入启动了 ROS 介导的细胞内信号传导，导致 KDR 和 Erk1/2 的激酶激活和磷酸化。由于内源性 VEGF 的高产量使 HNSCC 细胞对外源性 VEGF 的促有丝分裂作用产生抵抗，因此采用了 siRNA，抑制内源性 VEGF 的产生长达 96 小时。相对于转染载体匹配的对照，siRNA 处理的 HNSCC 细胞在 30nM 和 50nM siRNA 剂量下均显示增殖显着下降。向 siRNA 沉默的 HNSCC 细胞中添加外源 hrVEGF165（30ng/ml 和 50ng/ml）会导致细胞增殖呈剂量依赖性增加。细胞侵袭测定显示 VEGF 是一种有效的 HNSCC 化学引诱剂，并证明 VEGF 预处理增强了 HNSCC 细胞的侵袭性。来自 VEGF 攻击的 HNSCC 细胞的条件培养基显示明胶酶活性适度增加。我们的结果首次证明 HNSCC 细胞既是 VEGF 的靶标又是效应器。这些数据预示着VEGF靶向治疗有可能同时实现抗血管生成和抗肿瘤生成功能。
Former vascular endothelial growth factor (VEGF) - head and neck squamous cell carcinoma (HNSCC) studies have focused on VEGF’s contributions toward tumor-associated angiogenesis. Previously, we have shown that HNSCC cells produce high levels of VEGF. We therefore hypothesized that VEGF serves a biphasic role i.e. proangiogenic and protumorigenic in HNSCC pathogenesis. Western blots confirmed the presence of VEGF’s primary mitogenic receptors, VEGFR-2/KDR and VEGFR-1/Flt-1 in cultured HNSCC cells. Subsequent studies evaluated VEGF’s effects on HNSCC intracellular signaling, mitogenesis, invasive capacities and matrix metalloproteinases (MMPs) activities. Introduction of hrVEGF165 initiated ROS-mediated intracellular signaling, resulting in kinase activation and phosphorylation of KDR and Erk1/2. As high endogenous VEGF production rendered HNSCC cells refractory to exogenous VEGF’s mitogenic effects, siRNA was employed, inhibiting endogenous VEGF production for up to 96h. Relative to transfection vector matched controls, siRNA treated HNSCC cells showed a significant decrease in proliferation at both 30nM and 50nM siRNA doses. Addition of exogenous hrVEGF165 (30ng/ml and 50ng/ml) to siRNA-silenced HNSCC cells resulted in dose-dependent increases in cell proliferation. Cell invasion assays showed VEGF is a potent HNSCC chemoattractant and demonstrated that VEGF pretreatment enhanced invasiveness of HNSCC cells. Conditioned media from VEGF challenged HNSCC cells showed a moderate increase in gelatinase activity. Our results demonstrate, for the first time, that HNSCC cells are both targets and effectors for VEGF. These data introduce the prospect that VEGF targeted therapy has the potential to fulfill both anti-angiogenic and anti-tumorigenic functions.
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