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Sympathetic Neurotransmitters and Tumor Angiogenesis-Link between Stress and Cancer Progression.

Tilan J, Kitlinska J - J Oncol (2010)

Bottom Line: Dopamine (DA), on the other hand, interferes with VEGF signaling in endothelial cells, blocks its angiogenic functions and inhibits tumor growth.Another sympathetic neurotransmitter coreleased with NE, neuropeptide Y (NPY), directly stimulates angiogenesis.Hence, sympathetic neurotransmitters are powerful modulators of tumor growth and can become new targets in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, Georgetown University, Basic Science Building 231A, 3900 Reservoir Rd., NW, Washington, DC 20007, USA.

ABSTRACT
Recent evidence supports a longstanding hypothesis that chronic stress can influence tumor growth and progression. It has been shown that sympathetic neurotransmitters, such as catecholamines and neuropeptides, can affect both cancer cell growth and tumor vascularization. Depending on neurotransmitter and type of tumor, these effects can be both stimulatory and inhibitory. Norepinephrine (NE) and epinephrine (E) are potent stimulators of vascularization, acting both by inducing the release of angiogenic factors from tumor cells and directly on endothelial cell (EC) functions. As a result, activation of the adrenergic system increases growth of various types of tumors and has been shown to mediate stress-induced augmentation of tumor progression. Dopamine (DA), on the other hand, interferes with VEGF signaling in endothelial cells, blocks its angiogenic functions and inhibits tumor growth. Another sympathetic neurotransmitter coreleased with NE, neuropeptide Y (NPY), directly stimulates angiogenesis. However, proangiogenic actions of NPY can be altered by its direct effect on tumor cell proliferation and survival. In consequence, NPY can either stimulate or inhibit tumor growth, depending on tumor type. Hence, sympathetic neurotransmitters are powerful modulators of tumor growth and can become new targets in cancer therapy.

No MeSH data available.


Related in: MedlinePlus

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.
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fig1: 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.

Mentions: As summarized above, the discoveries of recent years provided a significant body of evidence confirming an important role of sympathetic neurotransmitters and, consequently, chronic stress in regulating of tumor vascularization (Figure 1). This research opens new avenues for developing novel therapeutics, as well as using already existing and well-characterized drugs, such as β-blockers and DA receptor agonists, in new clinical settings. This seems to be particularly important, since cancer diagnosis per se is usually a stressful event for the patient. However, careful consideration needs to be given to other actions of stress mediators, such as cancer-specific effects on tumor cells themselves, as well as changes in immune system, which can indirectly affect tumor development and progression. Finally, since patterns of neuro-hormonal activation vary with different types of stress [17], tumor exposure to particular stress mediators would vary, too. Thus, potential therapeutic value of modifying particular stress pathways may be dependent on a variety of factors.


Sympathetic Neurotransmitters and Tumor Angiogenesis-Link between Stress and Cancer Progression.

Tilan J, Kitlinska J - J Oncol (2010)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2874925&req=5

fig1: 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.
Mentions: As summarized above, the discoveries of recent years provided a significant body of evidence confirming an important role of sympathetic neurotransmitters and, consequently, chronic stress in regulating of tumor vascularization (Figure 1). This research opens new avenues for developing novel therapeutics, as well as using already existing and well-characterized drugs, such as β-blockers and DA receptor agonists, in new clinical settings. This seems to be particularly important, since cancer diagnosis per se is usually a stressful event for the patient. However, careful consideration needs to be given to other actions of stress mediators, such as cancer-specific effects on tumor cells themselves, as well as changes in immune system, which can indirectly affect tumor development and progression. Finally, since patterns of neuro-hormonal activation vary with different types of stress [17], tumor exposure to particular stress mediators would vary, too. Thus, potential therapeutic value of modifying particular stress pathways may be dependent on a variety of factors.

Bottom Line: Dopamine (DA), on the other hand, interferes with VEGF signaling in endothelial cells, blocks its angiogenic functions and inhibits tumor growth.Another sympathetic neurotransmitter coreleased with NE, neuropeptide Y (NPY), directly stimulates angiogenesis.Hence, sympathetic neurotransmitters are powerful modulators of tumor growth and can become new targets in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, Georgetown University, Basic Science Building 231A, 3900 Reservoir Rd., NW, Washington, DC 20007, USA.

ABSTRACT
Recent evidence supports a longstanding hypothesis that chronic stress can influence tumor growth and progression. It has been shown that sympathetic neurotransmitters, such as catecholamines and neuropeptides, can affect both cancer cell growth and tumor vascularization. Depending on neurotransmitter and type of tumor, these effects can be both stimulatory and inhibitory. Norepinephrine (NE) and epinephrine (E) are potent stimulators of vascularization, acting both by inducing the release of angiogenic factors from tumor cells and directly on endothelial cell (EC) functions. As a result, activation of the adrenergic system increases growth of various types of tumors and has been shown to mediate stress-induced augmentation of tumor progression. Dopamine (DA), on the other hand, interferes with VEGF signaling in endothelial cells, blocks its angiogenic functions and inhibits tumor growth. Another sympathetic neurotransmitter coreleased with NE, neuropeptide Y (NPY), directly stimulates angiogenesis. However, proangiogenic actions of NPY can be altered by its direct effect on tumor cell proliferation and survival. In consequence, NPY can either stimulate or inhibit tumor growth, depending on tumor type. Hence, sympathetic neurotransmitters are powerful modulators of tumor growth and can become new targets in cancer therapy.

No MeSH data available.


Related in: MedlinePlus