Multiple myeloma cells promote migration of bone marrow mesenchymal stem cells by altering their translation initiation.
The role of the bone marrow microenvironment in multiple myeloma pathogenesis and progression is well recognized. Indeed, we have shown that coculture of bone marrow mesenchymal stem cells from normal donors and multiple myeloma cells comodulated translation initiation. Here, we characterized the timeline of mesenchymal stem cells conditioning by multiple myeloma cells, the persistence of this effect, and the consequences on cell phenotype. Normal donor mesenchymal stem cells were cocultured with multiple myeloma cell lines (U266, ARP1) (multiple myeloma-conditioned mesenchymal stem cells) (1.5 h,12 h, 24 h, 48 h, and 3 d) and were assayed for translation initiation status (eukaryotic translation initiation factor 4E; eukaryotic translation initiation factor 4G; regulators: mechanistic target of rapamycin, MNK, 4EBP; targets: SMAD family 5, nuclear factor κB, cyclin D1, hypoxia inducible factor 1, c-Myc) (immunoblotting) and migration (scratch assay, inhibitors). Involvement of mitogen-activated protein kinases in mesenchymal stem cell conditioning and altered migration was also tested (immunoblotting, inhibitors). Multiple myeloma-conditioned mesenchymal stem cells were recultured alone (1-7 d) and were assayed for translation initiation (immunoblotting). Quantitative polymerase chain reaction of extracted ribonucleic acid was tested for microRNAs levels. Mitogen-activated protein kinases were activated within 1.5 h of coculture and were responsible for multiple myeloma-conditioned mesenchymal stem cell translation initiation status (an increase of >200%, P < 0.05) and elevated migration (16 h, an increase of >400%, P < 0.05). The bone marrow mesenchymal stem cells conditioned by multiple myeloma cells were reversible after only 1 d of multiple myeloma-conditioned mesenchymal stem cell culture alone. Decreased expression of microRNA-199b and microRNA-125a (an increase of <140%, P < 0.05) in multiple myeloma-conditioned mesenchymal stem cells supported elevated migration. The time- and proximity-dependent conditioning of normal donor mesenchymal stem cells in our model points to a dynamic interaction between multiple myeloma cells and the bone marrow niche, which causes profound changes in the nonmalignant bone marrow constituents. Future studies are warranted to identify clinically relevant means of blocking this crosstalk and improving multiple myeloma therapy.
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
Mahmoud
M
Dabbah
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
Oshrat
O
Attar-Schneider
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
Victoria
V
Zismanov
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and.
Shelly
S
Tartakover Matalon
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel; Internal Medicine Department, Meir Medical Center, Kfar Saba, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.
Michael
M
Lishner
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and druckerl@clalit.org.il.
Liat
L
Drucker
D050156:Adipogenesis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D039642:Eukaryotic Initiation Factors / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects; D055153:Stem Cell Niche; D013844:Thiazoles / Q000494:pharmacology
C517852:4EGI-1 compound; D039642:Eukaryotic Initiation Factors; D006835:Hydrazones; D035683:MicroRNAs; D013844:Thiazoles
MIR 125a-3p; MIR 199b-3b; cancer microenvironment; eIF4E; eIF4GI