Sympathetic Neurotransmitters and Tumor Angiogenesis—Link between Stress and Cancer Progression

Figure 1

Activation of sympathetic neurons results in release of various neurotransmitters—catecholamines and neuropeptides. Norepinephrine (NE) and Epinephrine (E), belonging to a family of catecholamines, activate their β-adrenoreceptors (ARs) expressed on tumor cells and stimulate release of angiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukins. Moreover, NE/E can directly induce endothelial cell (EC) proliferation and migration via their α-AR. Both of these processes lead to an increase in tumor vascularization. Adrenergic stimulation can also affect proliferation, survival, and invasiveness of cancer cells. This effect may be stimulatory or inhibitory, depending on tumor type. However, the proangiogenic actions of NE/E prevail over its direct effect on tumor cells. In consequence, adrenergic activation leads to an increase in tumor growth in most of the investigated tumor types. Another catecholamine, dopamine (DA), acts on its D2 receptors present on EC and interferes with VEGF signaling. As a result, dopamine reduces tumor vascularization and inhibits tumor growth. Neuropeptide Y (NPY), coreleased with NE from sympathetic nerves, directly stimulates EC proliferation and migration via its Y2Rs and increases tumor vascularization. However, NPY can also significantly alter the proliferation and survival of tumor cells. These direct actions of NPY on tumor cells are powerful enough to overcome its angiogenic activities. In consequence, the net effect of NPY varies in different types of tumors.