Title:Sympathetic Signaling in Angiogenesis: Implications for Cancer Progression
Volume: 8
Issue: 2
Author(s): Jason Tilan, Magdalena Czarnecka and Joanna Kitlinska
Affiliation:
Keywords:
Angiogenesis, catecholamines, hypoxia, neuropeptide Y, sympathetic neurotransmitters, tumor progression
Abstract: 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.
