神经生长因子通过激活多种途径促进乳腺癌血管生成。

BACKGROUND

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.

RESULTS

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.

CONCLUSIONS

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.

背景

尽管已有几种抗血管生成疗法被批准用于癌症治疗，但这些疗法的生存获益相对有限。因此，发现新的分子和/或更好地理解血管生成的信号通路对于治疗的改善至关重要。本研究旨在确定神经生长因子（NGF）在乳腺癌血管生成中的作用及其潜在的分子机制。

结果

我们表明，重组 NGF 和乳腺癌细胞产生的 NGF 均可刺激免疫缺陷小鼠的 Matrigel 塞中的血管生成。NGF 强烈促进内皮细胞的侵袭、索形成和单层通透性。此外，NGF 刺激的侵袭受其酪氨酸激酶受体（TrkA）和下游信号通路（如 PI3K 和 ERK）的控制，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 NGF 诱导的内皮细胞侵袭和体内血管生成。