Overproduction of VEGF165 concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling
Overproduction of VEGF165 concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling
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DOI：
10.1111/j.0022-202x.2004.23460.x
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发表时间：
2004-12-01
影响因子：
6.5
通讯作者：
Fabra, A
中科院分区：
文献类型：
--
作者：
Graells, J;Vinyals, A;Fabra, A
血管内皮生长因子(VEGF)是肿瘤相关血管生成的重要介质，与肿瘤转移密切相关。我们在这里报道，在黑色素瘤移植瘤中过表达的血管内皮生长因子(165)促进了肿瘤生长的加速和血管生成的增加以及自发转移的形成。此外，在A375黑色素瘤细胞中表达血管内皮生长因子受体(VEGFR)1、VEGFR2和神经亲和素-1。在这些细胞中强制过表达血管内皮生长因子诱导细胞生长，并通过依赖于丝裂原活化蛋白激酶信号通路的机制，在血清饥饿的培养物中触发生存活性。此外，这些效应依赖于MEK 1/2的活性。与对照组相比，激酶结构域区域特异性酪氨酸激酶抑制剂显著地将DNA合成减少到20%，尽管它们既不能完全抑制p44或p42磷酸化形式的细胞外信号调节蛋白激酶。这些抑制剂还引起Akt磷酸化水平的降低。我们观察到，在存在特定酪氨酸酶抑制剂的情况下，使用磷脂酰肌醇T-激酶(PI3K)特异性抑制剂治疗后，存活率显著降低。我们认为，过量表达的VEGF(165)及其受体通过MAPK和PI3K信号通路促进黑色素瘤细胞的生长和存活。这些数据支持至少在体外参与黑色素瘤生长和存活的依赖于血管内皮生长因子的内部自分泌环路机制。
Vascular endothelial growth factor (VEGF) is an important mediator of tumor-associated angiogenesis, and consequently it has been associated with metastasis. We report here that the overexpression of VEGF(165) in melanoma xenografts promotes an acceleration of tumor growth and an increase in angiogenesis as well as the spontaneous metastasis formation. In addition, VEGF receptors (VEGFR)1, VEGFR2 and neurophilin-1 are expressed in A375 melanoma cells. Forced overexpression of VEGF in these cells induces cell growth and triggers survival activity in serum-starved cultures, by a mechanism dependent on the mitogen-activating protein kinase signaling pathway. Furthermore, these effects are dependent MEK 1/2 activity. Kinase domain region-specific tyrosine kinase inhibitors dramatically reduced DNA synthesis to 20% with respect to the controls, although they did not completely suppress either the p44 or p42-phosphorylated forms of extracellular signal-regulated protein kinase. These inhibitors also provoked a decrease in Akt phosphorylation. We observed a dramatic reduction in survival after treatment with phosphatidylinositol T-kinase (PI3K)-specific inhibitor in the presence of specific tyrosinase inhibitors. We suggest that the overproduction of VEGF(165) concomitantly expressed with its receptors favors cell growth and survival of melanoma cells through MAPK and PI3K signaling pathways. These data support the involvement in melanoma growth and survival of a VEGF-dependent internal autocrine loop mechanism, at least in vitro.