Activation of the Kinin B1 Receptor by Its Agonist Reduces Melanoma Metastasis by Playing a Dual Effect on Tumor Cells and Host Immune Response
Activation of the Kinin B1 Receptor by Its Agonist Reduces Melanoma Metastasis by Playing a Dual Effect on Tumor Cells and Host Immune Response
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DOI：
10.3389/fphar.2019.01106
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发表时间：
2019-09-25
影响因子：
5.6
通讯作者：
Costa-Neto, Claudio M.
中科院分区：
文献类型：
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作者：
Maria, Andrea Gutierrez;Dillemburg-Pilla, Patricia;Costa-Neto, Claudio M.
转移性黑色素瘤是一种侵袭性皮肤癌，导致一半患者在诊断后 8-10 个月内死亡。激肽是与 B1 和 B2 受体相互作用的肽，发挥不同的生物学作用。我们研究了 B1 受体激动剂 des-Arg(9)-缓激肽 (DABK) 治疗是否对小鼠黑色素瘤诱导后肺转移的建立有影响。我们发现，与未接受治疗的小鼠相比，DABK 治疗的小鼠肺部转移集落数量较少，血管细胞粘附分子 1 (VCAM-1) 的表达减少，转移区域的 CD8(+)T 细胞募集增加。为了了解观察到的 DABK 的作用是否是由于肿瘤细胞或宿主中 B1 受体的激活所致，我们用 DABK 治疗野生型 (WT) 和激肽 B1 受体敲除 (B1(-/-)) 小鼠。 WT 和 B1(-/-) 小鼠之间肺部建立的黑色素瘤集落数量没有显着差异；然而，B1(-/-)小鼠表现出较高的VCAM-1表达和较低的CD8(+)T细胞浸润。总之，我们相信宿主体内激肽B1受体激动剂的激活能更有效地刺激免疫反应，促进CD8(+)T细胞募集至转移性肺并干扰VCAM-1表达。此外，DABK 治疗主要通过作用于肿瘤细胞来减少转移集落的建立；因此，这项研究为探索针对 B1 受体的转移性黑色素瘤治疗新方法带来了见解。
Metastatic melanoma is an aggressive type of skin cancer leading half of the patients to death within 8-10 months after diagnosis. Kinins are peptides that interact with B1 and B2 receptors playing diverse biological roles. We investigated whether treatment with B1 receptor agonist, des-Arg(9)-bradykinin (DABK), has effects in lung metastasis establishment after melanoma induction in mice. We found a lower number of metastatic colonies in lungs of DABK-treated mice, reduced expression of vascular cell adhesion molecule 1 (VCAM-1), and increased CD8(+)T-cell recruitment to the metastatic area compared to animals that did not receive treatment. To understand whether the effects of DABK observed were due to the activation of the B1 receptor in the tumor cells or in the host, we treated wild-type (WT) and kinin B1 receptor knockout (B1(-/-)) mice with DABK. No significant differences in the number of melanoma colonies established in lungs were seen between WT and B1(-/-)mice; however, B1(-/-)mice presented higher VCAM-1 expression and lower CD8(+)T-cell infiltration. In conclusion, we believe that activation of kinin B1 receptor by its agonist in the host stimulates the immune response more efficiently, promoting CD8(+)T-cell recruitment to the metastatic lungs and interfering in VCAM-1 expression. Moreover, treatment with DABK reduced establishment of metastatic colonies by mainly acting on tumor cells; hence, this study brings insights to explore novel approaches to treat metastatic melanoma targeting the B1 receptor.