Sphingosine-1-phosphate receptor 1 in classical Hodgkin lymphoma: assessment of expression and role in cell migration.
Sphingosine-1-phosphate receptor 1 in classical Hodgkin lymphoma: assessment of expression and role in cell migration.
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DOI：
10.1038/labinvest.2013.7
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发表时间：
2013-04
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经典霍奇金淋巴瘤（CHL）是一种异常B淋巴细胞（霍奇金 - 里德 - 施特恩伯格细胞）的肿瘤，据描述其具有典型的临床表现模式和扩散方式，常累及功能上相邻的淋巴结。尽管在理解CHL病理生理学方面取得了进展，但调节CHL中淋巴瘤细胞扩散的因素却知之甚少。1 - 磷酸鞘氨醇（S1P）是一种在血浆和淋巴液中高浓度存在的生物活性鞘脂，已知其主要通过S1PR1在调节淋巴细胞运输中起关键作用。在本研究中，我们探讨了S1P - S1PR1轴在霍奇金淋巴瘤细胞迁移中的作用以及S1PR1在CHL细胞系和临床病例中的表达。我们发现S1PR1在KM - H2和SUP - HD1霍奇金淋巴瘤细胞系中在mRNA和蛋白质水平均有表达。此外，在功能上，S1P强烈刺激这两种细胞系的迁移。S1P诱导的迁移被S1PR1拮抗剂VPC44116和S1PR1功能性拮抗剂FTY720 - P抑制，但被S1PR2特异性拮抗剂JTE013增强。我们还确定S1PR1通过异源三聚体G蛋白Gi和磷脂酰肌醇 - 3 - 激酶（PI3K）途径诱导KM - H2和SUP - HD1细胞迁移。对CHL样本组织的免疫组化评估显示，一部分病例（7/57；12%）在霍奇金 - 里德 - 施特恩伯格细胞中显示出S1PR1的强膜染色。
总之，我们的数据表明S1PR1是霍奇金 - 里德 - 施特恩伯格细胞上的一种功能性受体，它控制肿瘤细胞迁移，并且在一部分CHL病例中表达。鉴于S1PR1拮抗剂的可用性，其中一些已在临床上用于调节免疫系统，这些结果表明S1PR1可能成为治疗那些S1PR1阳性、难治性/复发性CHL病例的未来治疗靶点。
Classical Hodgkin lymphoma (CHL), a neoplasm of abnormal B lymphocytes (Hodgkin-Reed Sternberg cells), has been described to have a typical pattern of clinical presentation and dissemination often involving functionally contiguous lymph nodes. Despite the progress made in understanding CHL pathophysiology, the factors which regulate the spread of lymphoma cells in CHL are poorly understood. Sphingosine-1-Phosphate (S1P), a bioactive sphingolipid present at high concentrations in plasma and lymphatic fluid, is known to play a critical role in regulating lymphocyte trafficking mainly through S1PR1. In this study, we explore the role of the S1P-S1PR1 axis in Hodgkin lymphoma cell migration and the expression of S1PR1 in CHL cell lines and clinical cases. We found that S1PR1 is present in the KM-H2 and SUP-HD1 Hodgkin lymphoma cell lines at the mRNA and protein level. In addition, functionally, S1P potently stimulated migration of both cell lines. S1P-induced migration was inhibited by the S1PR1 antagonist, VPC44116 and the S1PR1 functional antagonist, FTY720-P, but was potentiated by the S1PR2 specific antagonist, JTE013. We also determined that S1PR1 induced migration in the KM-H2 and SUP-HD1 cells via the heterotrimeric G protein Gi and the phosphatidylinositol-3-kinase (PI3K) pathway. Immunohistochemical assessment of tissue from CHL samples revealed that a subset of cases (7/57; 12%) show strong, membranous staining for S1PR1 in Hodgkin-Reed Sternberg cells. Altogether our data indicate that S1PR1 is a functional receptor on Hodgkin-Reed Sternberg cells which governs tumor cell migration and is expressed in a subset of CHL cases. Given the availability of S1PR1 antagonists, some of which are used clinically for modulation of the immune system, these results suggest that S1PR1 could be a future therapeutic target in the treatment of those cases of S1PR1-positive, refractory/recurrent CHL.