norepinephrine beta3-Adrenoreceptors Melanoma

Norepinephrine and Beta3-Adrenoreceptors May Drive Melanoma Progression & Aggressiveness

Norepinephrine and Beta3-Adrenoreceptors – Melanoma

A report recently published in Oncotarget shows that the β3-adrenoreceptors are involved in melanoma aggressiveness, and that these receptors, expressed on several accessory cells, may orchestrate their function and thus, sustain melanoma progression.

Various biological effects of catecholamines in cancer cells have been associated to β-adrenergic receptors subfamily (β-ARs), composed of three members that signal through distinct downstream pathways. The three subtypes of β-ARs, β1, β2, and β3, are widely expressed in different tumors, such as those of the brain, lung, liver, kidney, adrenal gland, breast, ovary, prostate or lymphoid tissues. Primary melanoma cells express both β1 and β2-ARs and that β2-ARs are up-regulated in metastatic melanoma, with a strong correlation with malignancy.

In addition, β3-AR mRNA aberrant expression has been reported in human cancers, such as leukemia, vascular tumors and colon carcinoma. Recently, β3-ARs has been found to be expressed by murine melanoma B16F10 cells and by endothelial cells of the tumor vasculature. Finally, beside deregulation of β3-ARs expression, Trp64Arg β3-AR polymorphism has been associated with susceptibility to endometrial and breast cancers.

Preclinical studies suggest that β-blockers favorably impact on disease progression in several types of cancers, mainly by reducing metastases, tumor recurrence and mortality. The authors of the Oncotarget study previously demonstrated a significant activation of pro-tumorigenic biological responses induced by catecholamines in melanoma cells, severely inhibited by propranolol, a non-selective inhibitor that can block β-AR.

The ability of catecholamines to induce in melanoma cells the expression of the pro-inflammatory and pro-angiogenic interleukin-6 (IL-6), interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) prompted the authors to study the role of β-AR functions within tumor microenvironment.

Recent research also indicates that stress and stress mediators contribute to cancer development and/or progression.

It appears that in this process a major role is being played by the sympathetic nervous system through the effects of catecholamines, mainly norepinephrine (noradrenaline) and the beta-adrenergic system. The list of various tumors affected by catecholamines is rapidly growing, and this includes melanoma (Colucci R & Moretti S, J Cancer Res Clin Oncol. 2015 Nov 23).

In the Oncotarget study, Maura Calvani and colleagues from the University of Florence, Tuscany Tumor Institute, Florence, Italy demonstrate that β3-adrenoreceptors are expressed in human melanocytic lesions but also in stromal, endothelial and inflammatory cells, and that this expression positively correlated with this malignancy.

Thus, it appears that β-ARs are key molecular players of this malignancy’s aggressiveness and that their function is not restricted to cancer cells, but these receptors are strongly expressed and actively functional in a large set of tumor associated cells, such as cancer associated fibroblasts, macrophages and endothelial cells. Of note, both β-ARs are overexpressed in melanoma, with a clear correlation with malignancy.

β3-ARs appear to be the main responsible for instructing melanoma cells to respond to environmental cell signals, to sense cancer associated fibroblasts and macrophages enhancing their motility and stem-like traits.

Moreover, several accessory cells also express β3-AR and its functional activation plays an important role in eliciting stromal reactivity, to sustain secretion of proinflammatory cytokines and to drive de novo angio/vasculogenesis. All these events are promoting melanoma aggressiveness.

Importantly, tumor-associated accessory cells appeared to sustain secretion of proinflammatory cytokines and to drive de novo angio/vasculogenesis. This included the production of inteleukin (IL-6), IL-8 and vascular endothelial growth factor (VEGF)-A, and a role of β3-adrenoreceptors in the recruitment of fibroblasts, monocytes, bone marrow precursors (MSCs) and endothelial cells.

Also, β-ARs are also involved in monocytes recruitment induced by melanoma cells with a main involvement of β3-ARs over β2-ARs. Once recruited to the tumor site, monocytes differentiate into active macrophages, where they may play a multifaceted role for tumor progression.

These observations substantiate previous work suggesting the involvement of catecholamines in this cancer’s progression. This includes the ability of norepinephrine to upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines.

Of note, this study suggests that β-adrenoreceptor blockers may provide new therapeutic opportunities in melanoma, and, as we previously discussed, in general, beta blockers hold substantial potential for therapeutical interventions in cancer.

Source: Oncotarget. 2015, 6:4615-32.
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Cover Image (Right panel): Anatomy of the skin, showing the epidermis, dermis, and subcutaneous tissue. Melanocytes are in the layer of basal cells at the deepest part of the epidermis. From: Melanoma Treatment (PDQ®)–Patient Version, National Cancer Institute, Public domain.