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Abstract
Purpose: Mesenchymal Stem Cells (MSCs) are one of the essential members of Bone Marrow (BM) microenvironment and the cells affect normal and malignant cells in BM milieu. One of the most important hematological malignancies is Multiple Myeloma (MM). Numerous studies reported various effects of MSCs on myeloma cells. MSCs initiate various signaling pathways in myeloma cells, particularly NF-kβ. NF-kβ signaling pathway plays pivotal role in the survival, proliferation and resistance of myeloma cells to the anticancer drugs, therefore this pathway can be said to be a vital target for cancer therapy. This study examined the relationship between U266 cells and MSCs. Methods: U266 cells were cultured with Umbilical Cord Blood derived-MSCs (UCB-MSCs) and Conditioned Medium (C.M). Effect of UCB-MSCs and C.M on proliferation rate and CD54 expression of U266 cells were examined with MTT assay and Flowcytometry respectively. Furthermore, expression of CXCL1, PECAM-1, JUNB, CCL2, CD44, CCL4, IL-6, and IL-8 were analyzed by Real Time-PCR (RT-PCR). Moreover, status of p65 protein in NF-kβ pathway assessed by western blotting. Results: Our findings confirm that UCB-MSCs support U266 cells proliferation and they increase CD54 expression. In addition, we demonstrate that UCB-MSCs alter the expression of CCL4, IL-6, IL-8, CXCL1 and the levels of phosphorylated p65 in U266 cells. Conclusion: Our study provides a novel sight to the role of MSCs in the activation of NF-kβ signaling pathway. So, NF-kβ signaling pathway will be targeted in future therapies against MM.
Highlights
Multiple myeloma is an important hematological malignancy,[1] and is defined by the clonal proliferation of plasma cells
When MM cells are localized in the bone marrow, via the interaction of cell surface adhesion molecules, they bind to the bone marrow stromal cells (BMSC) and as a result, they trigger signaling pathways such as IL-6, SDF-1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), insulin-like growth factor-1 (IGF-1), tumor necrosis factor-α (TNF- α) and transforming growth factor-β (TGF- β) and they are involved in tumor cells proliferation.[9,15]
To determine the effect of Umbilical Cord Blood derived-MSCs (UCBMSCs) on CD54 expression, U266 cells were co-cultured with UCB-Mesenchymal Stem Cells (MSCs) and incubated for 24 hrs
Summary
Multiple myeloma is an important hematological malignancy,[1] and is defined by the clonal proliferation of plasma cells. BM cells secret different factors, such as VEGF and IGF1, can indirectly activate the NF-κβ pathway in MM cells.[3,10] in myeloma tumors, this signaling pathway supports cell survival, proliferation and resistance to anticancer drugs, the inhibition of NF-κβ is a vital option for anti-cancer therapies.[16] NF-κβ proteins consist of two great subfamilies: NF-κβ and ‘Rel’ molecules.[17] One of the most important proteins that plays a key role in this pathway is p65 This protein forms a dimer with p50, they attach to Ikappa B alpha (IκBα). This idea was examined using western blotting technique, in order to determine if p65 and phosphorylated p65 are activated through co-culturing that involves cell to cell interaction of UCB-MSCs with U266 cells, or not
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