ECTS Abstracts (2015) 1 P95

The KISS1 receptor [ndash] a new player in the tumour microenvironment of multiple myeloma

Julia Dotterweich1, Robert Tower3, Marc Müller3, Andreas Brandl2, Andreas Beilhack2, Sanjay Tiwari3, Claus Glüer3, Regina Ebert1, Franz Jakob1 & Norbert Schütze1

1Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany; 2Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany; 3Section Biomedical Imaging, Department of Diagnostic Radiology, University Hospital Schleswig-Holstein, Kiel, Germany.

Multiple myeloma (MM) is a haematological disease characterised by an aberrant proliferation of plasma cells within the bone marrow. As a consequence, 90% of all patients suffer from osteolytic bone loss, in turn promoting tumour growth in a “vicious cycle”. Of importance for disease progression is the direct cell-cell interaction between MM cells and the mesenchymal stem cells (MSCs)/osteogenic precursor cells (OPCs) residing within the tumour niche. To detect myeloma cell-specific interaction molecules on bone forming cells, we performed global gene expression analyses for MSCs and OPCs after myeloma cell contact. Whole genome analyses were performed using Affymetrix gene chip HG-U133 2.0 Plus Array and RNA (each n=5) from MSCs and OPCs that had been co-cultured for one day with the plasmacytoma cell line INA-6. Differentially expressed genes included angiogenic factors such as VEGF-A, and the adhesion molecule ICAM-1, both of which are of importance in MM disease progression. In addition, we identified the G-protein coupled receptor KISS1 receptor (KISS1R) as a gene upregulated in MSCs as well as OPCs after direct contact with INA-6 cells. Transwell experiments revealed that this upregulation is predominantly dependent on direct cell-cell contact. Upregulation was further confirmed at protein level using the fluorescently labelled ligand KISS1 (KISS1-Alexa 633) and a second, murine MM cell line. Furthermore, western blot analyses showed MM cell line-dependent expression of KISS1 as well as KISS1R. Treatment with KISS1 ligands Kp-10 and Kp-54 as well as a KISS1R antagonist had no impact on INA-6 cell or MSC proliferation. First experiments using KISS1-Alexa 633 in a murine model of MM bone disease showed an accumulation of fluorescence in tumour-burdened limbs compared with contralateral controls. These data suggest that the KISS1/KISS1R system may play a role in the crosstalk between MM and bone-forming cells thereby allowing the imaging of myeloma bone disease.

Disclosure: The authors declared no competing interests. This work was funded by The German Research Foundation within the Clinical Research Group-1586 SKELMET.

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