Sympathetic Signaling in Angiogenesis: Implications for Cancer Progression

Sympathetic neurotransmitters are known for their multiple and pleiotropic functions. Recently, regulation of tumor angiogenesis emerged as one of them. Norepinepherine and epinephrine have been shown to stimulate tumor vascularization via two independent mechanisms – induction of growth factor release from tumor and stromal cells, and a direct effect on endothelial cell (EC) proliferation. In contrast, their precursor, dopamine, interferes with vascular endothelial growth factor (VEGF) signaling in ECs and inhibits angiogenesis. Tumor vascularization can be also regulated by peptidergic neurotransmitters, such as neuropeptide Y (NPY), which acts as a potent angiogenic factor due to its direct stimulatory effect on EC proliferation, migration and capillary formation. The angiogenic activity of these neuronal factors is particularly apparent under the conditions of increased sympathetic activity during stress, or in tumors of sympathetic origin. However, there is also evidence indicating that basal sympathetic activity is essential for sustained growth of nonneuronal tumors. Importantly, sympathetic activity increases in hypoxia, which is a crucial factor inducing neovascularization. Moreover, in tumor cells, adrenergic stimulation up-regulates hypoxia-inducible factor 1α (HIF-1α) independently on oxygen levels, which mimics hypoxic conditions and increases the release of angiogenic factors. The pro- and antiangiogenic effects of sympathetic neurotransmitters are potent enough to alter rates of tumor growth and metastases, confirming their potential value as therapeutic targets. However, such therapy may be complicated by other activities of these neuronal factors, such as immunomodulation and direct effects on tumor cell functions, which are tumor specific and may both facilitate and inhibit tumor growth.