Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas
Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas
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DOI：
10.1158/0008-5472.can-03-3927
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发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Guzmán, M
中科院分区：
文献类型：
--
作者：
Blázquez, C;González-Feria, L;Guzmán, M
大麻素抑制小鼠肿瘤血管生成，但其抗血管生成作用的机制仍然未知。由于血管内皮生长因子（VEGF）通路在肿瘤血管生成中起着关键作用，在这里我们研究了大麻素是否影响它。胶质瘤降低了多种VEGF通路相关基因的表达。其他方法（ELISA，Western印迹和共聚焦显微镜）的使用提供了额外的证据，表明大麻素通过减少培养的神经胶质瘤细胞和小鼠神经胶质瘤中VEGF的产生和VEGF受体（VEGFR）-2（最突出的VEGF受体）的活化来抑制VEGF途径。大麻素诱导的VEGF产生和VEGFR-2活化的抑制在体外和体内通过药理学阻断神经酰胺生物合成而被废除。VEGF通路的这些变化被肿瘤大小的变化所掩盖。此外，肿瘤内给予大麻素δ（9）-四氢大麻酚给两名多形性胶质母细胞瘤（IV级星形细胞瘤）患者降低了肿瘤中的VEGF水平和VEGFR-2活化。由于阻断VEGF通路是目前最有前途的抗肿瘤方法之一，因此本研究结果为基于大麻素的治疗提供了一种新的药理学靶点。
Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Delta(9)-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.