The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Neue Stiftingtalstraße 6/II, 8010 Graz, Austria

Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria

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Division of General Otorhinolaryngology, Medical University of Graz, Auenbruggerplatz 26, 8036 Graz, Austria

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Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9/4, 8010 Graz, Austria

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Diagnostic & Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria

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Institute of Computational Biotechnology, Graz University of Technology, Petersgasse 14/V, 8010 Graz, Austria

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OMICS Center Graz, BioTechMed Graz, Stiftingtalstraße 24, 8010 Graz, Austria

Author to whom correspondence should be addressed.

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These authors contributed equally to this work.

Int. J. Mol. Sci. 2019, 20(19), 4740; https://doi.org/10.3390/ijms20194740

Received: 30 July 2019 / Revised: 19 September 2019 / Accepted: 21 September 2019 / Published: 24 September 2019

(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)

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Abstract

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas. View Full-Text

Keywords: DLBCL 1; CXCR4-CXCL12-axis 2; CXCR4 antagonist 3

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Pansy, K.; Feichtinger, J.; Ehall, B.; Uhl, B.; Sedej, M.; Roula, D.; Pursche, B.; Wolf, A.; Zoidl, M.; Steinbauer, E.; Gruber, V.; Greinix, H.T.; Prochazka, K.T.; Thallinger, G.G.; Heinemann, A.; Beham-Schmid, C.; Neumeister, P.; Wrodnigg, T.M.; Fechter, K.; Deutsch, A.J. The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro. Int. J. Mol. Sci. 2019, 20, 4740. https://doi.org/10.3390/ijms20194740

AMA Style

Pansy K, Feichtinger J, Ehall B, Uhl B, Sedej M, Roula D, Pursche B, Wolf A, Zoidl M, Steinbauer E, Gruber V, Greinix HT, Prochazka KT, Thallinger GG, Heinemann A, Beham-Schmid C, Neumeister P, Wrodnigg TM, Fechter K, Deutsch AJ. The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro. International Journal of Molecular Sciences. 2019; 20(19):4740. https://doi.org/10.3390/ijms20194740

Chicago/Turabian Style

Pansy, Katrin, Julia Feichtinger, Barbara Ehall, Barbara Uhl, Miriam Sedej, David Roula, Beata Pursche, Axel Wolf, Manuel Zoidl, Elisabeth Steinbauer, Verena Gruber, Hildegard T. Greinix, Katharina T. Prochazka, Gerhard G. Thallinger, Akos Heinemann, Christine Beham-Schmid, Peter Neumeister, Tanja M. Wrodnigg, Karoline Fechter, and Alexander J. Deutsch. 2019. "The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro" International Journal of Molecular Sciences 20, no. 19: 4740. https://doi.org/10.3390/ijms20194740

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The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

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