title: Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk.
abstract: 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 β2-adrenergic receptor (β2-AR), protein kinase A (PKA), and mTOR could reverse norepinephrine-induced Jagged 1 upregulation, indicating that the β2-AR-PKA-mTOR pathway participates in this process. Knockdown of Jagged 1 expression in breast cancer cells not only repressed norepinephrine-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 β2-AR-PKA-mTOR pathway.
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Limin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Que
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China sm200@sohu.com ningguo@nic.bmi.ac.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of PathophysiologyInstitute of Basic Medical Sciences, Beijing 100850, People's Republic of China sm200@sohu.com ningguo@nic.bmi.ac.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine
keywords: Jagged 1; Notch; angiogenesis; breast cancer; catecholamine; β2-AR