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.