Mesenchymal Stem Cells With Cancer-Associated Fibroblast-Like Phenotype Stimulate SDF-1/CXCR4 Axis to Enhance the Growth and Invasion of B-Cell Acute Lymphoblastic Leukemia Cells Through Cell-to-Cell Communication

Abstract

Background: Bone marrow mesenchymal stem cells (BM-MSCs) are the stromal cells in the leukemia microenvironment, and can obtain cancer-associated fibroblast (CAF)-like phenotype under certain conditions to further promote leukemia progression. However, the mechanism of MSCs with CAF-like phenotype interacting with leukemia cells in B-cell acute lymphoblastic leukemia (B-ALL) and promoting the progression of B-ALL remains unclear.Methods: Mesenchymal stem cells with CAF-like phenotype were obtained by treating MSCs with recombinant human transforming growth factor-β (rhTGF-β), hereafter referred to as TGF-β conditioned MSCs. In vivo mouse model experiments, in vitro transwell chamber experiments, three-dimensional (3D) cell culture models, lentiviral transfection and other experimental methods were used to investigate the possible mechanism of the interaction between TGF-β conditioned MSCs and leukemia cells in promoting the growth, migration and invasion of B-ALL cells.Results: Compared with untreated MSCs, TGF-β conditioned MSCs significantly promoted the growth and proliferation of leukemia cells in mice, and increased the expression of CXCR4 in tumor tissues. In vitro cell experiments, TGF-β conditioned MSCs obviously promoted the migration and invasion of Nalm-6/RS4;11 cells, which were effectively blocked by the CXCR4 inhibitor AMD3100, thereby inhibiting the secretion of MMP-9 in TGF-β conditioned MSCs and inhibiting the activation of the PI3K/AKT signaling pathway in leukemia cells. Further, findings were made that the interaction between TGF-β conditioned MSCs and leukemia cells were mediated by the interaction between the integrin receptor α5β1 on the surface of leukemia cells and the increased expression of fibronectin on TGF-β conditioned MSCs. AMD3100 could weaken such effect by reducing the expression of integrin α5β1 on leukemia cells. Further regulation of integrin β1 could effectively interfere with the interaction between TGF-β conditioned MSCs and leukemia cells.Conclusion: Mesenchymal stem cells with CAF-like phenotype could be a key factor in promoting the growth and invasion of B-ALL cells, and the SDF-1/CXCR4 axis might be a significant factor in mediating the communication of MSCs with CAF-like phenotype and leukemia cells. To prevent the progression of B-ALL cells, blocking the SDF-1/CXCR4 axis with AMD3100 or targeting integrin β1 might be a potential therapeutic strategy.

Mesenchymal stroma/stem cells: Haematologists’ friend or foe?

“…Another example of how the cross‐talk between MSCs and leukaemia cells can serve as a target for novel therapy was reported with the CXCR‐4 inhibitor AMD300. Treatment with AMD300 blocked the leukaemia growth and migration of leukaemic cells enhanced by MSCs 150 …”

“…Treatment with AMD300 blocked the leukaemia growth and migration of leukaemic cells enhanced by MSCs. 150 Finally, MSCs have been shown to modulate AML cell proliferation by the release of miRNA in small EVs. This has been shown to affect key regulatory pathways in leukaemia including PI3K/AKT/mTOR, affecting both proliferation and resistance to chemotherapy.…”

“…Treatment with AMD300 blocked the leukaemia growth and migration of leukaemic cells enhanced by MSCs. 150 …”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Other candidate cell types hypothesised as precursors of CAFs and factors stimulating their formation [59][60][61][62][63][64][65] are included in Table 1. Members of the TGF-β family seem to be the most frequently discussed in this context as inducers of the transition of precursor cells to myofibroblasts [66].…”

Cancer-associated fibroblasts in acute leukemia

“…Then, Pan et al. ( 145 , 146 ) found that TGF-β is a key factor for BM MSCs to obtain a CAF-like phenotype in a B-ALL microenvironment, which may interact with ALL cells through an SDF1-CXCR4 signaling axis to promote the progression of B-ALL. Using single-cell sequencing, Baryawno et al.…”