Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression

Table 1 Summary for the key soluble factors involved in multiple myeloma/bone marrow mesenchymal stem cells communication

Soluble factors	Origin	Function	Ref.
SDF1α	BMSCs	Chemoattractant of MM cell towards the BM microenvironment	[38]
IL-1β	MM cells	Act over BMSCs inducing the secretion of soluble factors, mainlyIL-6	[45]
IL-6	BMSCs	Closely related with cancer pathogenicity due to it proto-oncogenic and anti-apoptotic effect over MM cells	[46,47]
		Immunosuppressive effect over T cells
		Also related with bone destruction by inducing the expression of RANKL by the MM cells
VEGF	BM cells, MM cells	Promotes bone neovascularization, essential for tumour progression	[58]
RANKL	MM cells	Induce the commitment of the macrophage/monocyte precursor cells to the osteoclast lineage. Promoting indirectly bone destruction	[63]
DKK-1	MM cells	Disruptor of bone homeostasis by inhibiting BMSCs differentiation into osteoblasts	[66,67]

SDF1α: Stromal cell derived factor 1α; BM-MSC: Bone marrow mesenchymal stem cells; MM: Multiple myeloma; IL: Interleukin; RANKL: Receptor activator of NFκΒ ligand; VEGF: Vascular endothelial growth factor; DKK-1: Dickkopf-1.

Table 2 Summary of evidence about the relevance of different cargo molecules in the extracellular vesicles of multiple myeloma cells and bone marrow mesenchymal stem cells s to the progression of multiple myeloma

	Function	Ref.
MM-EVs cargo
lncRNA RUNX2-AS1	Form a RNA duplex with RUNX2 premRNA, reducing the osteogenic activity in MSCs	[76]
miR-146a	Increase the secretion of several cytokines in BM-MSCs that favor MM cell viability and migration and induce CAF transformation	[78]
DKK-1	Lower expression of OSX, COL1A1 and ALP in osteoblast precusor cell line (MC3t3-E1)	[72]
MSC-EVs cargo
mir-15a	Promote MM cell proliferation and dissemination to other niches	[70]
miR-483-5p	Induce MM cell proliferation and reduced apoptosis	[79]
miR-155	Reduce MM cell apoptosis and augment expression of stemness maintenance and drug resistance markers	[81]

EVs: Extracellular vesicles; MM: Multiple myeloma; BM-MSC: Bone marrow mesenchymal stem cells; CAF: Cancer associated fibroblast; DKK-1: Dickkopf-1; OSX: Osterix; COL1A1: Collagen 1A1; ALP: Alkaline phosphatase.