β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment

Abstract

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of β-adrenergic signaling in enhancing tumor growth through β2-adrenoreceptors (β2-ARs) has been confirmed in different cancer models, but the role played by the β3-adrenergic receptor (β3-AR) has recently emerged. Previous studies showed that β3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological β3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that β3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of β3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that β3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression.

Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus

“…In this respect, it has recently been demonstrated that β3-AR is widely expressed in the most frequent neoplasms occurring in pregnant women [22] and its blockade reduces cancer progression [14][15][16][17][18]. In particular, SR59230A, administered intratumorally at 5 mg/kg, has been shown to decrease melanoma growth by inducing neoplastic cell death and inhibiting tumor vascularization [15] while, when administered intraperitoneally at 10 mg/kg and 20 mg/kg, it reduced neuroblastoma [18] and melanoma [35] progression, respectively. These latter studies, indicating that SR59230A exerted marked anticancer effects upon intraperitoneal administration at the noted dosage [35], were the background to the present experiments in which we investigated the effects on the DA of SR59230A, administered intraperitoneally at 10, 20 and 40 mg/kg, both in acute and chronic mode.…”

“…In particular, SR59230A, administered intratumorally at 5 mg/kg, has been shown to decrease melanoma growth by inducing neoplastic cell death and inhibiting tumor vascularization [15] while, when administered intraperitoneally at 10 mg/kg and 20 mg/kg, it reduced neuroblastoma [18] and melanoma [35] progression, respectively. These latter studies, indicating that SR59230A exerted marked anticancer effects upon intraperitoneal administration at the noted dosage [35], were the background to the present experiments in which we investigated the effects on the DA of SR59230A, administered intraperitoneally at 10, 20 and 40 mg/kg, both in acute and chronic mode. Of note, this study was carried out on healthy dams, without evaluating the anticancer properties of SR59230A.…”

β3-Adrenoreceptors as ROS Balancer in Hematopoietic Stem Cell Transplantation

“…In this review, we aimed to suggest that the β3-AR agonist could be tested in the first phase of transplantation to maintain low to moderate levels of ROS, and to preserve stemness and long-term differentiation. When HSCs start to differentiate, ROS must be kept at moderate/high levels to stimulate hematopoietic differentiation, as previously demonstrated in melanoma [ 96 , 99 ]. However, as the molecular biomarkers have not yet been identified, it is hard to state the necessary dose and timing of agonists/antagonists’ administration.…”

The Autonomic Regulation of Tumor Growth and the Missing Links

“…Interestingly, Adrβ3 inhibition in myeloid cells switches macrophage and neutrophil phenotypes to immunocompetent M1 and N1 types, respectively, indicating additional mechanisms of Adrβ3 blockers in checking tumors (29). Adrβ3 signals also enrich stromal population by recruiting and maintaining hemopoietic (HSC) and mesenchymal stem cells (MSC) favoring tumor aggression, while Adrβ3 blockade was shown to promote local differentiation of HSC to lymphoid/myeloid lineages and MSC to adipocyte lineages in melanoma favoring a less aggressive tumor milieu (30).…”