β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment
β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment
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DOI：
10.3390/ijms21041420
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Favre, Claudio
中科院分区：
文献类型：
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作者：
Calvani, Maura;Bruno, Gennaro;Favre, Claudio
尽管越来越多的证据表明肿瘤微环境（TME）中的肿瘤干细胞（CSC）利基在维持实体瘤的进展中起着至关重要的作用，但参与这种调节的几个分子参与者仍然未知。β -肾上腺素能信号通过β 2-肾上腺素受体（β 2- ar）促进肿瘤生长的作用已在不同的癌症模型中得到证实，但β 3-肾上腺素能受体（β 3-AR）所起的作用最近才被发现。先前的研究表明，β 3-AR通过激活TME中的不同基质细胞促进肿瘤生长，并通过炎症、血管生成和免疫耐受导致黑色素瘤恶性进展。在B16黑色素瘤小鼠中，药理学β 3-AR阻断能够降低CSC标记物的表达，并诱导TME中造血亚群的分化表型。特别是，肿瘤块的细胞荧光分析（FACS）显示β 3-AR拮抗剂SR59230A促进造血分化，这表明淋巴细胞/造血干细胞（hsc）和髓系祖细胞/ hsc的比例增加，并增加Ter119和自然杀伤（NK）前体细胞以及粒细胞前体细胞的数量，表明肿瘤组织内造血活跃。此外，β 3-AR的药理拮抗作用诱导间充质干细胞（MSC）分化为脂肪细胞，减少了这些细胞对干细胞室的潜在更新。本研究表明，以牺牲干细胞特性为代价，通过诱导不同基质细胞的分化来阻断TME中的β 3-AR，可能对控制黑色素瘤的进展具有有利作用。
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 beta-adrenergic signaling in enhancing tumor growth through beta 2-adrenoreceptors (beta 2-ARs) has been confirmed in different cancer models, but the role played by the beta 3-adrenergic receptor (beta 3-AR) has recently emerged. Previous studies showed that beta 3-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 beta 3-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 beta 3-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 beta 3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that beta 3-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.