Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells
Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells
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DOI：
10.1111/jpi.12007
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发表时间：
2013-05-01
影响因子：
10.3
通讯作者：
Cos, Samuel
中科院分区：
文献类型：
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作者：
Alvarez-Garcia, Virginia;Gonzalez, Alicia;Cos, Samuel
褪黑素通过干扰雌激素信号通路发挥抑制乳腺癌的作用。褪黑素通过调节影响肿瘤微环境的细胞因子，减少人乳腺癌细胞、周围成纤维细胞和瘤周内皮细胞中雌激素的生物合成。这种荷尔蒙还在肿瘤组织中发挥抗血管生成活性。在这项工作中，我们的目的是研究褪黑素对乳腺癌细胞中血管内皮生长因子(VEGF)的调节作用。为此，我们将人乳腺癌细胞(MCF-7)与人脐静脉内皮细胞(HUVECs)进行共培养。血管内皮细胞生长因子可促进HUVECs的增殖，褪黑素(1 MM)可拮抗此作用。褪黑素可降低MCF-7细胞中血管内皮生长因子的产生和血管内皮生长因子基因表达。MCF-7细胞与人脐静脉内皮细胞共培养可刺激内皮细胞增殖，增加培养上清液中的血管内皮生长因子水平。褪黑素对HUVECs增殖的刺激作用和对共培养上清液中血管内皮生长因子蛋白水平的影响均被抵消。MCF-7细胞条件培养液可促进HUVEC增殖，抗血管内皮生长因子抗体和1 mM褪黑素可明显拮抗这一作用。这些结果提示，褪黑素可能通过下调人乳腺癌细胞中血管内皮生长因子的表达，从而降低血管内皮细胞周围的血管内皮生长因子水平，从而在恶性上皮细胞与近端内皮细胞之间的旁分泌相互作用中发挥作用。较低的血管内皮生长因子水平可能在减少恶性肿瘤细胞附近的雌激素产生细胞数量以及减少肿瘤血管生成方面发挥重要作用。
Melatonin exerts oncostatic effects on breast cancer by interfering with the estrogen-signaling pathways. Melatonin reduces estrogen biosynthesis in human breast cancer cells, surrounding fibroblasts and peritumoral endothelial cells by regulating cytokines that influence tumor microenvironment. This hormone also exerts antiangiogenic activity in tumoral tissue. In this work, our objective was to study the role of melatonin on the regulation of the vascular endothelial growth factor (VEGF) in breast cancer cells. To accomplish this, we cocultured human breast cancer cells (MCF-7) with human umbilical vein endothelial cells (HUVECs). VEGF added to the cultures stimulated the proliferation of HUVECs and melatonin (1mm) counteracted this effect. Melatonin reduced VEGF production and VEGF mRNA expression in MCF-7 cells. MCF-7 cells cocultured with HUVECs stimulated the endothelial cells proliferation and increased VEGF levels in the culture media. Melatonin counteracted both stimulatory effects on HUVECs proliferation and on VEGF protein levels in the coculture media. Conditioned media from MCF-7 cells increased HUVECs proliferation, and this effect was significantly counteracted by anti-VEGF and 1mm melatonin. All these findings suggest that melatonin may play a role in the paracrine interactions between malignant epithelial cells and proximal endothelial cells through a downregulatory action on VEGF expression in human breast cancer cells, which decrease the levels of VEGF around endothelial cells. Lower levels of VEGF could be important in reducing the number of estrogen-producing cells proximal to malignant cells as well as decreasing tumoral angiogenesis.