TY - JOUR
T1 - Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells –Implications for myeloma bone disease
AU - Dotterweich, Julia
AU - Schlegelmilch, Katrin
AU - Keller, Alexander
AU - Geyer, Beate
AU - Schneider, Doris
AU - Zeck, Sabine
AU - Tower, Robert J.J.
AU - Ebert, Regina
AU - Jakob, Franz
AU - Schütze, Norbert
N1 - Funding Information:
The authors thank the German Research Foundation (DFG) for funding this work that is associated within the Clinical Research Group-FOR1586 SKELMET (Schu 747/10-1 , EB 447/3-1 ). We are indebted to Dr. Kurt Bommert (Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg) for providing the INA-6 cell line, Dr. Wolfgang Feichtinger (Institute of Human Genetics, University of Würzburg) for sequence analyses, PD Dr. Ludger-Klein Hitpass (Institute of Cell Biology (Tumor Research), University of Duisburg-Essen) for array analyses, Christian Linden (Cell sorting core facility, Institute of Virology and Immunobiology, University of Würzburg) for his technical assistance in flow cytometer, the orthopedic surgeons (Orthopedic Clinic, Würzburg) for supplying us with cancellous bone, and Jutta Schneidereit as well as Viola Zehe (Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg) for the preparation of the MSC. In addition, we thank the statistical consulting service of the University of Würzburg for support as well as Solange Le Blanc and Dr. Stephanie Graser for proofreading.
Publisher Copyright:
© 2016 The Authors
PY - 2016/12/1
Y1 - 2016/12/1
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 INA-6 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.
AB - 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 INA-6 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 - Angiopoietin-like 4
KW - Bone disease
KW - Gene expression profiling
KW - Mesenchymal stem cells
KW - Multiple myeloma
KW - Osteogenic precursor cells
UR - http://www.scopus.com/inward/record.url?scp=84989315124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84989315124&partnerID=8YFLogxK
U2 - 10.1016/j.bone.2016.08.006
DO - 10.1016/j.bone.2016.08.006
M3 - Article
C2 - 27519972
AN - SCOPUS:84989315124
SN - 8756-3282
VL - 93
SP - 155
EP - 166
JO - Bone
JF - Bone
ER -