Sphingosine-1-phosphate receptor 1 in classical Hodgkin lymphoma: assessment of expression and role in cell migration

Abstract

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.

Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations

“…S1PR1 was found mutated in four tumor samples derived from two patients. It encodes for the sphingosine-1-phosphate receptor 1, which has been shown expressed in mantle zone B cells and MCL [26, 27]. Mutations in the CARD11 gene, which is known to be recurrently targeted in DLBCL and in splenic marginal zone lymphomas [28, 29], were discovered in three tumor samples derived from two patients.…”

SPNS2 promotes the malignancy of colorectal cancer cells via regulating Akt and ERK pathway

“…Downregulation of S1PR1 by miRNAs could inhibit cell proliferation in hepatocellular carcinoma and nasopharyngeal carcinoma . Additionally, the Classical Hodgkin Lymphoma cell migration was promoted by S1P/S1PR1 axis . The population and expansion of cancer stem cells can be enhanced by S1P‐stimulated S1PR3 via activating Notch signalling .…”

Anti-leukemic activity of a four-plant mixture in a leukemic rat model

“…Once lymphocytes reach circulation, the surface expression of S1PR1 is rapidly downregulated (Lo, Xu, Proia, & Cyster, 2005) as a result of the high amounts of S1P in the lymph and blood (Pappu et al, 2007). S1P1 has been reported to be expressed in several hematological malignancies including expression by classical Hodgkin's lymphoma cells, B cell chronic lymphocytic leukemia, and activated B cell-like diffuse large B cell lymphoma (Capitani et al, 2012;Liu et al, 2012;Kluk et al, 2013). Expression of S1PR by blood cancer cells may directly regulate their survival by controlling the localization of cells within permissive environments such as the lymph nodes (Blaho & Hla, 2014).…”

“…S1P has been implicated in disorders such as cancer and inflammatory diseases, and several agonists and antagonists have been developed and are in clinical trials that target S1PR1 (Kunkel et al, 2013). Examples of these drugs include Fingolimod and phosphorylated Fingolimod (S1PR1 agonist and functional antagonist) that inhibits lymphocyte trafficking and decreases colitis and cancer progression (Mandala et al, 2002;Brinkmann et al, 2010;Lee et al, 2010;Liang et al, 2013), VPC44116 (S1PR1 antagonist) that decreases Hodgkin's lymphoma (Kluk et al, 2013), and W146 (S1PR1 antagonist) that induces lymphopenia (Tarrason et al, 2011;Sanna et al, 2006). It is possible that the plant mixture under study contains some S1PR1 agonists/antagonists that regulate S1PR1 expression and the number of lymphocytes in the DMBAtreated rats.…”