Bone marrow mesenchymal stem cells in microenvironment transform into cancer-associated fibroblasts to promote the progression of B-cell acute lymphoblastic leukemia

Pan, Chengyun; Liu, Ping; Ma, Dan; Zhang, Siyu; Ni, Ming; Fang, Qin; Wang, Jishi

doi:10.1016/j.biopha.2020.110610

Cited by 15 publications

(28 citation statements)

References 43 publications

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“…In the present study, BM-MSCs were derived from bone marrow mononuclear cells of patients with B-ALL. The phenotypic characteristics, adipogenic and osteogenic differentiation functions thereof have been verified in previous research by the present authors ( Pan et al, 2020 ). MSCs with CAF-like phenotype were obtained from BM-MSCs of the same B-ALL patient after stimulation with rhTGF-β for 48–72 h (TGF-β conditioned MSCs).…”

Section: Resultssupporting

confidence: 89%

“…In the present study, MSCs with CAF-like phenotype expressed all the cell surface markers commonly used to mark MSCs, but the adipogenic differentiation function was weakened. And the expression levels of the biomarkers of MSCs and MSCs with CAF-like phenotype were confirmed to be different in a previous study by the present authors (Pan et al, 2020), indicating that there is a certain difference there between. In the vivo experiments, MSCs with CAF-like phenotype promoted tumor formation and stimulated tumor growth in mice, which is consistent with previously published studies on solid tumors (Teng et al, 2016).…”

Section: Discussionsupporting

confidence: 78%

“…Over the years, the protective role of CAFs in several hematological malignancies has been gradually revealed ( Frassanito et al, 2016 ; Zhai et al, 2016 ; Burt et al, 2019 ). Notably, in a previous in vitro study of the present authors, findings were made that bone marrow mesenchymal stem cells (BM-MSCs) could acquire CAF-like phenotype in the B-ALL microenvironment, and the TGF-β was a key factor for MSCs to obtain the CAF-like phenotype, with the latter potentially being a significant component in promoting the migration and invasion of B-ALL cells ( Pan et al, 2020 ). However, there are a number of issues that remain unclear, such as how the MSCs with CAF-like phenotype interact with B-ALL cells and how the progression of B-ALL is promoted.…”

Section: Introductionmentioning

confidence: 77%

“…MSCs with CAF-like phenotype were obtained from BM-MSCs of the same B-ALL patient after stimulation with rhTGF-β for 48–72 h (TGF-β conditioned MSCs). The morphological characteristics and the expression level of biomarkers were used to identify and distinguish MSCs and MSCs with CAF-like phenotype ( Pan et al, 2020 ). In the present study, the results of flow cytometry revealed that TGF-β conditioned MSCs highly expressed CD90, CD105 and CD44, but did not express CD34, CD45, and CD19 ( Supplementary Figure S1A ), which was consistent with the immunophenotype of MSCs ( Pan et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…The complete medium of adult BM-MSCs (Saiye, Shanghai, China) was used for the cultivation of MSCs. MSCs with CAF-like phenotype were obtained by adding recombinant human transforming growth factor-β (rhTGF-β) (10 ng/ml) to stimulate MSCs for 48–72 h ( Pan et al, 2020 ), which referred to as TGF-β conditioned MSCs.…”

Section: Methodsmentioning

confidence: 99%

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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

Pan

Fang

Liu

et al. 2021

Front. Cell Dev. Biol.

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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.

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 78%