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

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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.

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CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression.

Xueqing Sun, Guangcun Cheng, Mingang Hao … (2010)

Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.

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Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia.

Laurie Sehn, Jane C. Donaldson, Mukesh Chhanabhai … (2005)

For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC). We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with "B" symptoms or bulky [> 10 cm] disease) DLBCL. A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P = .002) and overall survival (risk ratio, 0.40; 95% CI, 0.27 to 0.61, P < .0001) were significantly improved in the postrituximab group. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of progression-free survival (risk ratio, 0.59; 95% CI, 0.41 to 0.85; P = .005) and overall survival (risk ratio, 0.43; 95% CI, 0.29 to 0.66; P < .001). The benefit of treatment in the postrituximab era was present regardless of age. The addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL patients of all ages in the province of BC.

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Regulation of the Chemokine Receptor CXCR4 by Hypoxia

Tiziana Schioppa, Badarch Uranchimeg, Alessandra Saccani … (2003)

Cell adaptation to hypoxia (Hyp) requires activation of transcriptional programs that coordinate expression of genes involved in oxygen delivery (via angiogenesis) and metabolic adaptation (via glycolysis). Here, we describe that oxygen availability is a determinant parameter in the setting of chemotactic responsiveness to stromal-derived factor 1 (CXCL12). Low oxygen concentration induces high expression of the CXCL12 receptor, CXC receptor 4 (CXCR4), in different cell types (monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells), which is paralleled by increased chemotactic responsiveness to its specific ligand. CXCR4 induction by Hyp is dependent on both activation of the Hyp-inducible factor 1 α and transcript stabilization. In a relay multistep navigation process, the Hyp–Hyp-inducible factor 1 α–CXCR4 pathway may regulate trafficking in and out of hypoxic tissue microenvironments.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 24 September 2019

Publication date Collection: October 2019

Volume: 20

Issue: 19

Electronic Location Identifier: 4740

Affiliations

[1 ]Division of Hematology, Medical University Graz; Auenbruggerplatz 38, 8036 Graz, Austria; katrin.pansy@ 123456medunigraz.at (K.P.); barbara.ehall@ 123456medunigraz.at (B.E.); barbara.uhl@ 123456medunigraz.at (B.U.); Beata_Prusche@ 123456yahoo.de (B.P.); hildegard.greinix@ 123456medunigraz.at (H.T.G.); KatharinaTheresa.Prochazka@ 123456klinikum-graz.at (K.T.P.); peter.neumeister@ 123456medunigraz.at (P.N.); fechterkaroline@ 123456gmail.com (K.F.)

[2 ]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; julia.feichtinger@ 123456medunigraz.at

[3 ]Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria; miriam.sedej@ 123456medunigraz.at (M.S.); david.roula@ 123456medunigraz.at (D.R.); akos.heinemann@ 123456medunigraz.at (A.H.)

[4 ]Division of General Otorhinolaryngology, Medical University of Graz, Auenbruggerplatz 26, 8036 Graz, Austria; axel.wolf@ 123456klinikum-graz.at

[5 ]Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9/4, 8010 Graz, Austria; manuel.zoidl@ 123456tugraz.at (M.Z.); t.wrodnigg@ 123456tugraz.at (T.M.W.)

[6 ]Diagnostic & Research Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria; elisabeth.steinbauer@ 123456klinikum-graz.at (E.S.); verena.gruber@ 123456klinikum-graz.at (V.G.); christine.beham@ 123456medunigraz.at (C.B.-S.)

[7 ]Institute of Computational Biotechnology, Graz University of Technology, Petersgasse 14/V, 8010 Graz, Austria; gerhard.thallinger@ 123456tugraz.at

[8 ]OMICS Center Graz, BioTechMed Graz, Stiftingtalstraße 24, 8010 Graz, Austria

Author notes

[* ]Correspondence: alexander.deutsch@ 123456medunigraz.at ; Tel.: +43-316-385-72816

[†]

These authors contributed equally to this work.

Author information

Katrin Pansy https://orcid.org/0000-0001-6972-4937

Barbara Uhl https://orcid.org/0000-0002-8460-8771

David Roula https://orcid.org/0000-0003-0472-6784

Gerhard G. Thallinger https://orcid.org/0000-0002-2864-5404

Akos Heinemann https://orcid.org/0000-0002-8554-2372

Alexander JA. Deutsch https://orcid.org/0000-0003-0914-2809

Article

Publisher ID: ijms-20-04740

DOI: 10.3390/ijms20194740

PMC ID: 6801866

PubMed ID: 31554271

SO-VID: f856d514-56a9-4d6d-9b2e-e1f9213f738c

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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

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Neuronal Signaling

Most cited references 58

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression.

Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia.

Regulation of the Chemokine Receptor CXCR4 by Hypoxia

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