TY  - JOUR
A1  - Dotterweich, Julia
A1  - Schlegelmilch, Katrin
A1  - Keller, Alexander
A1  - Geyer, Beate
A1  - Schneider, Doris
A1  - Zeck, Sabine
A1  - Tower, Robert J. J.
A1  - Ebert, Regina
A1  - Jakob, Franz
A1  - Schütze, Norbert
T1  - Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells-implications for myeloma bone disease
JF  - Bone
N2  - Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.
KW  - marrow stromal cells
KW  - Endothelial growth-factor
KW  - precedes multiple-myeloma
KW  - monoclonial gammopathy
KW  - in-vitro
KW  - mesenchymal stem-cells
KW  - undetermined significance
KW  - angiogenic cytokines
KW  - peripheral-blood
KW  - gene-expression
KW  - Multiple myeloma
KW  - Bone disease
KW  - Angiopoietin-like 4
KW  - Gene expression profiling
KW  - Mesenchymal stem cells
KW  - Osteogenic precursor cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186688
VL  - 93
ER  - 
TY  - JOUR
A1  - Dotterweich, Julia
A1  - Tower, Robert J.
A1  - Brandl, Andreas
A1  - Müller, Marc
A1  - Hofbauer, Lorenz C.
A1  - Beilhack, Andreas
A1  - Ebert, Regina
A1  - Glüer, Claus C.
A1  - Tiwari, Sanjay
A1  - Schütze, Norbert
A1  - Jakob, Franz
T1  - The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease
JF  - PLoS One
N2  - Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.
KW  - multiple myeloma Lesions
KW  - fluorescence microscopy
KW  - biomarkers Myelomas
KW  - bone imaging
KW  - myeloma cells
KW  - fluorescent dyes
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146960
VL  - 11
IS  - 5
ER  -