Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice

Abstract

Over the past few decades, there has been growing interest in understanding the molecular mechanisms of cancer pathogenesis and progression, as it is still associated with high morbidity and mortality. Current management of large bone sarcomas typically includes the complex therapeutic approach of limb salvage or sacrifice combined with pre- and postoperative multidrug chemotherapy and/or radiotherapy, and is still associated with high recurrence rates. The development of cellular strategies against specific characteristics of tumour cells appears to be promising, as they can target cancer cells selectively. Recently, Mesenchymal Stromal Cells (MSCs) have been the subject of significant research in orthopaedic clinical practice through their use in regenerative medicine. Further research has been directed at the use of MSCs for more personalized bone sarcoma treatments, taking advantage of their wide range of potential biological functions, which can be augmented by using tissue engineering approaches to promote healing of large defects. In this review, we explore the use of MSCs in bone sarcoma treatment, by analyzing MSCs and tumour cell interactions, transduction of MSCs to target sarcoma, and their clinical applications on humans concerning bone regeneration after bone sarcoma extraction.

Keywords: 5-FC, 5-fluorocytosine; AAT, a1-antitrypsin; APCs, antigen presenting cells; ASC, adipose-derived stromal/stem cells; Abs, antibodies; Ang1, angiopoietin-1; BD, bone defect; BMMSCs, bone marrow-derived mesenchymal stromal cells; Biology; Bone; CAM, cell adhesion molecules; CCL5, chemokine ligand 5; CCR2, chemokine receptor 2; CD, classification determinants; CD, cytosine deaminase; CLUAP1, clusterin associated protein 1; CSPG4, Chondroitin sulfate proteoglycan 4; CX3CL1, chemokine (C-X3-C motif) ligand 1; CXCL12/CXCR4, C-X-C chemokine ligand 12/ C-X-C chemokine receptor 4; CXCL12/CXCR7, C-X-C chemokine ligand 12/ C-X-C chemokine receptor 7; CXCR4, chemokine receptor type 4; Cell; DBM, Demineralized Bone Marrow; DKK1, dickkopf-related protein 1; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; FGF-2, fibroblast growth factors-2; FGF-7, fibroblast growth factors-7; GD2, disialoganglioside 2; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; HMGB1/RACE, high mobility group box-1 protein/ receptor for advanced glycation end-products; IDO, indoleamine 2,3-dioxygenase; IFN-α, interferon alpha; IFN-β, interferon beta; IFN-γ, interferon gamma; IGF-1R, insulin-like growth factor 1 receptor; IL-10, interleukin-10; IL-12, interleukin-12; IL-18, interleukin-18; IL-1b, interleukin-1b; IL-21, interleukin-21; IL-2a, interleukin-2a; IL-6, interleukin-6; IL-8, interleukin-8; IL11RA, Interleukin 11 Receptor Subunit Alpha; MAGE, melanoma antigen gene; MCP-1, monocyte chemoattractant protein-1; MMP-2, matrix metalloproteinase-2; MMP2/9, matrix metalloproteinase-2/9; MRP, multidrug resistance protein; MSCs, mesenchymal stem/stromal cells; Mesenchymal; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; OPG, osteoprotegerin; Orthopaedic; PBS, phosphate-buffered saline; PDGF, platelet-derived growth factor; PDX, patient derived xenograft; PEDF, pigment epithelium-derived factor; PGE2, prostaglandin E2; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B; PTX, paclitaxel; RANK, receptor activator of nuclear factor kappa-B; RANKL, receptor activator of nuclear factor kappa-B ligand; RBCs, red blood cells; RES, reticuloendothelial system; RNA, ribonucleic acid; Regeneration; SC, stem cells; SCF, stem cells factor; SDF-1, stromal cell-derived factor 1; STAT-3, signal transducer and activator of transcription 3; Sarcoma; Stromal; TAAs, tumour-associated antigens; TCR, T cell receptor; TGF-b, transforming growth factor beta; TGF-b1, transforming growth factor beta 1; TNF, tumour necrosis factor; TNF-a, tumour necrosis factor alpha; TRAIL, tumour necrosis factor related apoptosis-inducing ligand; Tissue; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WBCs, white blood cell; hMSCs, human mesenchymal stromal cells; rh-TRAIL, recombinant human tumour necrosis factor related apoptosis-inducing ligand.

Fig. 1

MSC pro-tumorigenic effect main pathways.

Fig. 2

MSC anti-tumorigenic and pro-apoptotic effect.