Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease
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Antonio Garcia-Gomez1,2,3, Javier De Las Rivas1, Enrique M. Ocio1,2, Elena Díaz-Rodríguez1, Juan C. Montero1, Montserrat Martín1,3, Juan F. Blanco2, Fermín M. Sanchez-Guijo2,3, Atanasio Pandiella1,2, Jesús F. San Miguel1,2,3 and Mercedes Garayoa1,2,3
1 Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
2 Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
3 Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
Mercedes Garayoa, email:
Keywords: multiple myeloma, bone marrow mesenchymal stromal cells, tumor-stroma interactions, gene expression profiling, co-culture techniques, myeloma bone disease
Received: January 6, 2014 Accepted: June 2, 2014 Published: June 4, 2014
Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.
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