NDLI: Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo.

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Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo.

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Llama-derived single variable domains (nanobodies) directed against chemokine receptor CXCR7 reduce head and neck cancer cell growth in vivo.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Smit, Martine J. Maussang, David Gonzalez-pajuelo, Maria Stigter-van Walsum, Marijke Vosjan, Maria Merchiers, Pascal Mujic-delic, Azra Vanlandschoot, Peter Stortelers, Catelijne Van Roy, Maarten Van Rompaey, Philippe Descamps, Francis J. Vischer, Henry F. Van Dongen, Guus A. M. S.
Description	Author Affiliation: Maussang D ( From the Amsterdam Institute for Molecules Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.)
Abstract	The chemokine receptor CXCR7, belonging to the membrane-bound G protein-coupled receptor superfamily, is expressed in several tumor types. Inhibition of CXCR7 with either small molecules or small interference (si)RNA has shown promising therapeutic benefits in several tumor models. With the increased interest and effectiveness of biologicals inhibiting membrane-bound receptors we made use of the 'Nanobody platform' to target CXCR7. Previously we showed that Nanobodies, i.e. immunoglobulin single variable domains derived from naturally occurring heavy chain-only camelids antibodies, represent new biological tools to efficiently tackle difficult drug targets such as G protein-coupled receptors. In this study we developed and characterized highly selective and potent Nanobodies against CXCR7. Interestingly, the CXCR7-targeting Nanobodies displayed antagonistic properties in contrast with previously reported CXCR7-targeting agents. Several high affinity CXCR7-specific Nanobodies potently inhibited CXCL12-induced ß-arrestin2 recruitment in vitro. A wide variety of tumor biopsies was profiled, showing for the first time high expression of CXCR7 in head and neck cancer. Using a patient-derived CXCR7-expressing head and neck cancer xenograft model in nude mice, tumor growth was inhibited by CXCR7-targeting Nanobody therapy. Mechanistically, CXCR7-targeting Nanobodies did not inhibit cell cycle progression but instead reduced secretion of the angiogenic chemokine CXCL1 from head and neck cancer cells in vitro, thus acting here as inverse agonists, and subsequent angiogenesis in vivo. Hence, with this novel class of CXCR7 inhibitors, we further substantiate the therapeutic relevance of targeting CXCR7 in head and neck cancer.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	41
Volume Number	288
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2013-10-11
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Head And Neck Neoplasms Immunology Receptors, CXCR Single-Domain Antibodies Xenograft Model Antitumor Assays Animals Arrestins Metabolism Binding, Competitive Camelids, New World Cell Line, Tumor Chemokine CXCL12 Pharmacology Gene Expression Regulation, Neoplastic HEK293 Cells Pathology Prevention & Control Mice Mice, Nude NIH 3T3 Cells Radioligand Assay Genetics Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Drug Effects Tumor Burden Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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