Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways.
Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways.
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DOI：
10.1186/1476-4598-9-157
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发表时间：
2010-06-22
期刊：
影响因子：
37.3
通讯作者：
Le Bourhis X
中科院分区：
文献类型：
--
作者：
Romon R;Adriaenssens E;Lagadec C;Germain E;Hondermarck H;Le Bourhis X
尽管几种抗血管生成疗法已被批准用于治疗癌症，但这些疗法的生存益处相对较小。因此，发现新的分子和/或更好地理解血管生成的信号传导途径对于治疗改进至关重要。本研究的目的是确定神经生长因子（NGF）参与乳腺癌血管生成和潜在的分子机制。我们发现，重组神经生长因子和乳腺癌细胞产生的神经生长因子刺激免疫缺陷小鼠的基质胶栓塞血管生成。神经生长因子强烈增加侵袭，索形成和单层通透性的内皮细胞。此外，NGF刺激的侵袭是在其酪氨酸激酶受体（TrkA）和下游信号通路如PI 3 K和ERK的控制下，导致基质金属蛋白酶2和一氧化氮合酶的激活。有趣的是，NGF增加了内皮细胞和乳腺癌细胞中VEGF的分泌。用中和抗体抑制VEGF，可减少约一半的体内NGF诱导的内皮细胞侵袭和血管生成。我们的研究结果提供了直接的证据，神经生长因子可能是一个重要的刺激乳腺癌血管生成。因此，神经生长因子，以及激活的信号通路，应被视为潜在的新的靶点，抗血管生成治疗乳腺癌。
Although several anti-angiogenic therapies have been approved in the treatment of cancer, the survival benefits of such therapies are relatively modest. Discovering new molecules and/or better understating signaling pathways of angiogenesis is therefore essential for therapeutic improvements. The objective of the present study was to determine the involvement of nerve growth factor (NGF) in breast cancer angiogenesis and the underlying molecular mechanisms. We showed that both recombinant NGF and NGF produced by breast cancer cells stimulated angiogenesis in Matrigel plugs in immunodeficient mice. NGF strongly increased invasion, cord formation and the monolayer permeability of endothelial cells. Moreover, NGF-stimulated invasion was under the control of its tyrosine kinase receptor (TrkA) and downstream signaling pathways such as PI3K and ERK, leading to the activation of matrix metalloprotease 2 and nitric oxide synthase. Interestingly, NGF increased the secretion of VEGF in both endothelial and breast cancer cells. Inhibition of VEGF, with a neutralizing antibody, reduced about half of NGF-induced endothelial cell invasion and angiogenesis in vivo. Our findings provided direct evidence that NGF could be an important stimulator for breast cancer angiogenesis. Thus, NGF, as well as the activated signaling pathways, should be regarded as potential new targets for anti-angiogenic therapy against breast cancer.
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