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

Abstract

Bone marrow microenvironment is essential for leukemia cells to survive and escape the killing effect of chemotherapeutics. Cancer-associated fibroblasts (CAFs) are the dominant stromal cells in tumor microenvironment (TME), but their role in B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. Here, RT-PCR and Western blotting in bone marrow mononuclear cells revealed higher proportions of CAFs markers α-SMA and FAP in the newly diagnosed and relapsed B-ALL patients. In vitro experiments, bone marrow mesenchymal stem cells (BM-MSCs) acquired a CAFs phenotype after co-culture with leukemia cells, which produced high level of tumor-promoting growth factors and reduced the daunorubicin (DNR)-induced damage to B-ALL cells. As for its mechanism, CAFs activation was mediated by TGF-β up-regulation in the co-culture system, and TGF-β triggered MSCs conversion into CAFs relying on the SDF-1/CXCR4 pathway. Further LY2109761 and AMD3100 effectively decreased the activation of CAFs through inhibiting TGF-β receptor and CXCR4. Comparative experiments with MSCs and transformed CAFs prompted that CAFs had more obvious effect than MSCs on stimulating leukemia progression through accelerating leukemia cell migration and invasion. These results clarified the important role of CAFs in B-ALL progression and the possible mechanisms of CAFs activation in leukemia microenvironment, which might provide a theoretical basis for B-ALL patients to find more effective targeted therapies targeting the bone marrow microenvironment.

• Authors: Chengyun Pan, Ping Liu, Dan Ma, Siyu Zhang, Ming Ni, Qin Fang, Jishi Wang
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 130 Pg. 110610 (Oct 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 34321159 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Benzylamines
• CXCL12 protein, human
• CXCR4 protein, human
• Chemokine CXCL12
• Cyclams
• LY2109761
• Pyrazoles
• Pyrroles
• Receptors, CXCR4
• Transforming Growth Factor beta
• plerixafor

Topics

• Benzylamines (pharmacology)
• Cancer-Associated Fibroblasts (metabolism, pathology)
• Cell Line, Tumor
• Chemokine CXCL12 (metabolism)
• Cyclams (pharmacology)
• Disease Progression
• Humans
• Mesenchymal Stem Cells (drug effects, metabolism)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (etiology, metabolism, pathology)
• Pyrazoles (pharmacology)
• Pyrroles (pharmacology)
• Receptors, CXCR4 (metabolism)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment (drug effects)