Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates.

Autor: Wakileh GA; Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.; Department of Urology, University Hospital Ulm, Ulm, Germany., Bierholz P; Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany., Kotthoff M; Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany., Skowron MA; Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany., Bremmer F; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Stephan A; Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany., Anbuhl SM; Amsterdam Institute for Molecular and Life Sciences, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, Amsterdam, Netherlands.; QVQ Holding BV, Utrecht, the Netherlands., Heukers R; Amsterdam Institute for Molecular and Life Sciences, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, Amsterdam, Netherlands.; QVQ Holding BV, Utrecht, the Netherlands., Smit MJ; Amsterdam Institute for Molecular and Life Sciences, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, Amsterdam, Netherlands., Ströbel P; Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany., Nettersheim D; Department of Urology, Urological Research Laboratory, Translational UroOncology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany. Daniel.Nettersheim@med.uni-duesseldorf.de.; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany. Daniel.Nettersheim@med.uni-duesseldorf.de.
Jazyk: angličtina
Zdroj: Experimental hematology & oncology [Exp Hematol Oncol] 2023 Nov 23; Vol. 12 (1), pp. 96. Date of Electronic Publication: 2023 Nov 23.
DOI: 10.1186/s40164-023-00460-9
Abstrakt: Being stimulated by the chemokine CXCL12, the CXCR4 / CXCR7 cascade is involved in tumor proliferation, migration, and metastasis. The interaction between CXCL12, secreted by cells from the microenvironment, and its receptors is complex and has been ascribed to promote chemotherapy resistance. However, the role of this signaling axis and its targetability in germ cell tumors (GCT) is not fully understood. Thus, this study investigated the therapeutic efficacy of a nanobody-drug-conjugate targeting CXCR4 (CXCR4-NDC) and functionally characterized this signaling pathway in GCT using small molecule inhibitors and nanobodies. As shown by diminished cell viability, enhanced apoptosis induction, and detection of mitotic catastrophes, we confirmed the cytotoxic efficacy of the CXCR4-NDC in CXCR4 + -GCT cells (i.e. seminoma and yolk-sac tumor), while non-malignant CXCR4 - -fibroblasts, remained largely unaffected. Stimulation of CXCR4 +  / CXCR7 + -GCT cells with CXCL12 resulted in an enhanced proliferative and migratory capacity, while this effect could be reverted using CXCR4 inhibitors or a CXCR7-nanobody. Molecularly, the CXCR4 / CXCR7-signaling cascade could be activated independently of MAPK (ERK1 / 2)-phosphorylation. Although, in CXCR4 -  / CXCR7 - -embryonal carcinoma cells, CXCR7-expression was re-induced upon inhibition of ERK1 / 2-signaling. This study identified a nanobody-drug-conjugate targeting CXCR4 as a putative therapeutic option for GCT, i.e. seminoma and yolk-sac tumors. Furthermore, this study shed light on the functional role of the CXCR4 / CXCR7 / CXCL12-signaling cascade in GCT, demonstrating an important influence on proliferation and migration.
(© 2023. The Author(s).)
Databáze: MEDLINE
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