Exosomes from BM-MSCs promote acute myeloid leukemia cell proliferation, invasion and chemoresistance via upregulation of S100A4

Abstract

Background BM-MSCs play an important role in cancer development through the release of cytokines or exosomes. Studies have shown that extracellular exosomes derived from BM-MSCs are a key pro-invasive factor. However, how BM-MSC-exos influence AML cell proliferation, invasion and chemoresistance remains poorly understood. Methods We isolated exosomes from BM-MSCs and used electron microscopy, particle size separation and western blots to identify the exosomes. The invasion of leukemia cells was observed with a transwell assay. The stemness traits and chemoresistance of the leukemia cells were detected by FCM, colony formation and CCK-8 assays. TCGA database was used to investigate the prognostic relevance of S100A4 and its potential role in AML. Results In this study, we found that BM-MSC-exos increased the metastatic potential, maintained the stemness and contributed to the chemoresistance of leukemia cells. Mechanistically, BM-MSC-exos promoted the proliferation, invasion and chemoresistance of leukemia cells via upregulation of S100A4. Downregulating S100A4 clearly suppressed the proliferation, invasion, and chemoresistance of leukemia cells after treatment with BM-MSC-exos. Bioinformatic analysis with data in TCGA database showed that S100A4 was associated with poor prognosis in AML patients, and functional enrichment revealed its involvement in the processes of cell–cell adhesion and cytokine regulation. Conclusions S100A4 is vital in the BM-MSC-exo-driven proliferation, invasion and chemoresistance of leukemia cells and may serve as a potential target for leukemia therapy.

[Retracted] Mesenchymal Stem Cell‐Derived Exosomes and Their Potential Agents in Hematological Diseases

“…According to published papers, evidence underscored the hypothesis that the mechanisms of MSCs, at least in leukemia, were attributed mainly to secreting function by exosomes shuttle [ 39 , 40 , 105 ]. With regard to AML, Lyu and colleagues recently highlighted the profound impact of MSC-exosomes on leukemia cells [ 106 ]. They examined the efficacy after treatment with MSC-exosomes and found that MSC-exosomes functionally promoted the proliferation, invasion, and chemoresistance of tumor cells via upregulation of S100A4, a typical member of the S100 family of calcium-binding proteins [ 106 ].…”

“…Oxidative Medicine and Cellular Longevity to AML, Lyu and colleagues recently highlighted the profound impact of MSC-exosomes on leukemia cells [106]. They examined the efficacy after treatment with MSCexosomes and found that MSC-exosomes functionally promoted the proliferation, invasion, and chemoresistance of tumor cells via upregulation of S100A4, a typical member of the S100 family of calcium-binding proteins [106].…”

“…Oxidative Medicine and Cellular Longevity to AML, Lyu and colleagues recently highlighted the profound impact of MSC-exosomes on leukemia cells [106]. They examined the efficacy after treatment with MSCexosomes and found that MSC-exosomes functionally promoted the proliferation, invasion, and chemoresistance of tumor cells via upregulation of S100A4, a typical member of the S100 family of calcium-binding proteins [106]. Releasing risk factors by cargoes of MSC-exosomes, including TGFB1, miR-155, and miR-375, was another underlying mechanism for chemoresistance within the niche of AML [33].…”

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

“…Interestingly, EVs from healthy or leukemic niches reveal differences in chemoprotection. The EVs from AML-MSCs (AML-MSC-EVs) protect AML cells against cytarabine or AC220 (FLT3 kinase suppressor) and contain higher levels of well-known clinical risk factors, such as transforming growth factor-β1 (TGF-β1) and miR-155, compared to EVs from healthy donors [ 47 ]. Consistently, AML-MSC-EVs regulate the AML progression promoting cell proliferation, migration, and invasion, inhibiting GSK3β expression and activating Wnt/β-catenin signaling in AML cells [ 48 ].…”

Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

“…Recently, several studies have probed into mechanisms of MSC-EVs in AML resistance. Lyu et al [ 117 ] reported that exosome-treatment of AML cells acquired enhanced resistance to cytarabine by up-regulating S100A4, an important effector participated in cell adherence and cytokine regulation. Another study revealed that after exosomes encapsulating fibroblast growth factor 2 (FGF2) in bone marrow stromal cells, they were subsequently endocytosed by leukemic cells and protected leukemic cells from tyrosine kinase inhibitors (TKIs) [ 118 ].…”