Norepinephrine – 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.
Read More: ncbi.nlm.nih.gov
Updates
A 2020 review published in the Open Access journal MDPI summarizes data of different experimental studies demonstrating the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression.
Some background given by the authors: The β-adrenergic receptors (β-ARs) have been identified as the main responsible actors of stress-enhanced tumor-related pathways. Although initially two β-AR subtypes have been identified, β1-AR and β2-AR, the existence of the third β-AR subtype, firstly described as “atypical β-adrenoreceptor”, and named β3-AR, has been acknowledged much later. All three β-ARs can be activated by noradrenaline (norepinephrine) and adrenaline (epinephrine), although with different affinity. The two catecholamines are, indeed, equipotent at the β1-AR, while adrenalin is 100-fold more selective for β2-AR. On the contrary, noradrenaline is more potent than adrenaline as a β3-AR agonist.
As per the authors due to the lack of clinical studies using selective β3-AR antagonists in humans, the role of β3-AR subtype in melanoma cancer has not been clarified so far at clinical level; nevertheless, its contribution to processes related to melanoma progression is becoming evident, as suggested by pre-clinical evidences.
For example, in mice, a 2019 study indicates that the β3-AR blockade increased the number of NK cells and lymphocytes CD8+ as well as their cytotoxicity, M1/M2 macrophages ratio and N1 granulocytes, while it abrogated Treg and MDSC sub-populations in tumor mass. Other studies suggest that the pharmacological β3-AR blockade was able to reduce the expression of cancer stem cell (CSC) markers, and to induce a differentiated phenotype of numerous hematopoietic progenitors recruited in in tumor and stromal cells of melanoma microenvironment (TME).
Another study indicates that in human A375 melanoma cells, β3-AR stimulation through the selective agonist BRL37344 was able to induce a shift from an oxidative to a glycolytic metabolism, sustaining a metabolic process typical of tumor cells and known as Warburg effect.
Preclinical data summarized in this review have clearly suggested that β3-AR is able to modulate the activity of different cells in the melanoma microenvironment and, consequently, its blockade exerts an important anti-tumor action by affecting multiple pro-tumor signaling pathways
Despite studies investigating the role of β3-AR at clinical level still not being available, the expression of this receptor has been confirmed in melanoma biopsies from different patients. Although β3-AR was expressed in all examined melanocytic lesions, its expression level, taking into account both staining intensity and percentage of positive cells, was significantly higher in malignant compared to benign lesions.
A 2024 review published in the journal Melanoma Research concludes that the local and systemic implications of chronic adrenergic signaling across all receptor subtypes in relation to the immunomodulation of melanoma remains a topic of active translational and clinical investigation. Current clinical observations suggest that these pathways appear to be driven largely in part via expression of the β2-AR subtype, and increasing pre-clinical evidence suggests the β3-AR pathways may also be involved.
Given traditional nonselective β-AR blocking agents do not inhibit the β3-AR subtype, introducing β3-AR blockade with or without both β2-AR blockade and/or ICI in the clinical setting for patients with melanoma is an exciting concept anticipated to provide additional valuable insights into the key mechanisms of adrenergic signaling as they relate to the anti-tumoral immune response. Similarly, the utility of combining β-AR blockade with alternative standard of care ICI for advanced melanoma, including anti-CTLA4 and the newly approved anti-LAG3 agents, are also in need of further investigation.
Moreover, the modulation of β-AR signaling is anticipated to provide a safe and cost-effective means of optimizing endogenous immune surveillance while enhancing the anti-tumoral immune response of current standard-of-care treatments for patients with melanoma as well as many other cancer types.
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, https://www.cancer.gov/types/skin/patient/melanoma-treatment-pdq Public domain.
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