Oncotarget

Research Papers:

CCR10/CCL27 crosstalk contributes to failure of proteasome-inhibitors in multiple myeloma

Shanmugapriya Thangavadivel, Claudia Zelle-Rieser, Angelika Olivier, Benno Postert, Gerold Untergasser, Johann Kern, Andrea Brunner, Eberhard Gunsilius, Rainer Biedermann, Roman Hajek, Ludek Pour, Wolfgang Willenbacher, Richard Greil and Karin Jöhrer _

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Oncotarget. 2016; 7:78605-78618. https://doi.org/10.18632/oncotarget.12522

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Abstract

Shanmugapriya Thangavadivel1, Claudia Zelle-Rieser1, Angelika Olivier1, Benno Postert1, Gerold Untergasser1,2, Johann Kern2, Andrea Brunner3, Eberhard Gunsilius2, Rainer Biedermann4, Roman Hajek5, Ludek Pour5, Wolfgang Willenbacher6, Richard Greil1,7,8,9, Karin Jöhrer1

1Tyrolean Cancer Research Institute, Innsbruck, Austria

2Laboratory of Tumor Angiogenesis and Tumorbiology, Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria

3Department of Pathology, Medical University Innsbruck, Innsbruck, Austria

4Department of Orthopedic Surgery, Medical University Innsbruck, Innsbruck, Austria

5Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic, Department of Hematooncology, Faculty of Medicine, University of Ostrava and University Hospital Ostrava, Ostrava, Czech Republic

6Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria

7Salzburg Cancer Research Institute-Laboratory of Immunological and Molecular Cancer Research, Salzburg, Austria

8Third Medical Department at The Paracelsus Medical University Salzburg, Austria

9Cancer Cluster Salzburg (CCS), Salzburg, Austria

Correspondence to:

Karin Jöhrer, email: Karin.Joehrer@tkfi.at

Keywords: myeloma, CCR10, CCL27, drug resistance, stroma cells

Received: July 04, 2016     Accepted: October 03, 2016     Published: October 08, 2016

ABSTRACT

The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.

In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.

From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.


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