Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk
Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk
复制标题
DOI：
10.1530/erc-14-0236
复制
发表时间：
2014-10-01
影响因子：
3.9
通讯作者：
Guo, Ning
中科院分区：
文献类型：
--
作者：
Chen, Hongyu;Liu, Dan;Guo, Ning
血管生成是侵袭性肿瘤生长、进展和转移的重要因素。多种促血管生成机制参与肿瘤血管生成。在这项研究中，我们发现，神经递质去甲肾上腺素上调VEGF（VEGFA）在乳腺癌细胞中的表达，去甲肾上腺素处理的乳腺癌细胞的培养上清液促进内皮细胞的毛细血管样网络的形成。然而，去甲肾上腺素的作用进一步增强时，内皮细胞与乳腺癌细胞共培养，表明肿瘤细胞-内皮细胞接触在去甲肾上腺素诱导的肿瘤血管生成的关键作用。有趣的是，去甲肾上腺素显着诱导Notch途径的激活，这是一种细胞接触介导的细胞间信号传导途径，并与肿瘤细胞-基质细胞相互作用和血管生成密切相关，在与乳腺癌细胞共培养的内皮细胞中。此外，Notch配体Jagged 1的表达在乳腺癌细胞中的mRNA和蛋白水平上被去甲肾上腺素显著上调。β 2-肾上腺素能受体（β 2-AR）、蛋白激酶A（PKA）和mTOR的抑制剂可逆转去甲肾上腺素诱导的Jagged 1上调，表明β 2-AR-PKA-mTOR通路参与了这一过程。乳腺癌细胞中Jagged 1表达的敲除不仅抑制了共培养内皮细胞中去甲肾上腺素诱导的Notch通路的激活，而且明显削弱了去甲肾上腺素对毛细血管样芽形成的影响。这些数据表明，由Jagged 1/Notch细胞间信号传导介导的肿瘤血管生成由去甲肾上腺素激活的β 2-AR-PKA-mTOR途径控制。
Angiogenesis is an important factor in invasive tumor growth, progression, and metastasis. Multiple proangiogenic mechanisms are involved in tumor angiogenesis. In this study, we showed that the neurotransmitter norepinephrine upregulated VEGF (VEGFA) expression in breast cancer cells and that the culture supernatant from norepinephrine-treated breast cancer cells promoted the formation of the capillary-like network of endothelial cells. However, the effects of norepinephrine were further enhanced when the endothelial cells were cocultured with breast cancer cells, indicating a critical role of tumor cell-endothelial cell contacts in norepinephrine-induced tumor angiogenesis. Interestingly, norepinephrine dramatically induced the activation of the Notch pathway, which is a cell-contact-mediated intercellular signaling pathway and tightly linked to tumor cell-stromal cell interaction and angiogenesis, in the endothelial cells that had been cocultured with breast cancer cells. Furthermore, the expression of the Notch ligand Jagged 1 was significantly upregulated by norepinephrine at both mRNA and protein levels in breast cancer cells. Inhibitors of beta 2-adrenergic receptor (beta 2-AR), protein kinase A (PKA), and mTOR could reverse norepinephrine-induced Jagged 1 upregulation, indicating that the beta 2-AR-PKA-mTOR pathway participates in this process. Knockdown of Jagged 1 expression in breast cancer cells not only repressed norepine-phrine-induced activation of the Notch pathway in cocultured endothelial cells but also evidently impaired the effects of norepinephrine on capillary-like sprout formation. These data demonstrate that tumor angiogenesis mediated by the Jagged 1/Notch intercellular signaling is governed by the norepinephrine-activated beta 2-AR-PKA-mTOR pathway.