title: Multiple myeloma and bone marrow mesenchymal stem cells' crosstalk: Effect on translation initiation.
abstract: Multiple myeloma (MM) malignant plasma cells reside in the bone marrow (BM) and convert it into a specialized pre-neoplastic niche that promotes the proliferation and survival of the cancer cells. BM resident mesenchymal stem cells (BM-MSCs) are altered in MM and in vitro studies indicate their transformation by MM proximity is within hours. The response time frame suggested that protein translation may be implicated. Thus, we assembled a co-culture model of MM cell lines with MSCs from normal donors (ND) and MM patients to test our hypothesis. The cell lines (U266, ARP-1) and BM-MSCs (ND, MM) were harvested separately after 72 h of co-culture and assayed for proliferation, death, levels of major translation initiation factors (eIF4E, eIF4GI), their targets, and regulators. Significant changes were observed: BM-MSCs (ND and MM) co-cultured with MM cell lines displayed elevated proliferation and death as well as increased expression/activity of eIF4E/eIF4GI; MM cell lines co-cultured with MM-MSCs also displayed higher proliferation and death rates coupled with augmented translation initiation factors; in contrast, MM cell lines co-cultured with ND-MSCs did not display elevated proliferation only death and had no changes in eIF4GI levels/activity. eIF4E expression was increased in one of the cell lines. Our study demonstrates that there is direct dialogue between the MM and BM-MSCs populations that includes translation initiation manipulation and critically affects cell fate. Future research should be aimed at identifying therapeutic targets that may be used to minimize the collateral damage to the cancer microenvironment and limit its recruitment into the malignant process. © 2015 Wiley Periodicals, Inc.
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Oshrat
authors: O
authors: Attar-Schneider
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Victoria
authors: V
authors: Zismanov
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Mahmoud
authors: M
authors: Dabbah
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Shelly
authors: S
authors: Tartakover-Matalon
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Liat
authors: L
authors: Drucker
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Internal Medicine, Meir Medical Center, Kfar Saba, Israel.
authors: Michael
authors: M
authors: Lishner
mesh_terms: D000368:Aged; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D039561:Eukaryotic Initiation Factor-4E / Q000032:analysis / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis; D059016:Tumor Microenvironment
chemical_list: C113920:EIF4G1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G
keywords: cancer microenvironment; eIF4E; eIF4GI; mesenchymal stem cells; multiple myeloma; translation initiation