Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors
Abstract
:1. Introduction
2. Hematological Tumors: Types and Features
2.1. Leukemia
2.1.1. Acute Myeloid Leukemia
2.1.2. Chronic Myeloid Leukemia
2.1.3. Acute Lymphoblastic Leukemia
2.1.4. Chronic Lymphocytic Leukemia
2.2. Lymphoma
2.3. Multiple Myeloma
3. Drug Resistance
3.1. Downregulation of Drug Targets
3.2. Cell Cycle Regulation, Apoptosis, and DNA Repair
3.3. Reduction of the Concentration of Anticancer Drugs
3.4. Modulation of the Tumor Microenvironment
4. Tumor Microenvironment
4.1. Tumor Microenvironment in Hematopoietic Tumors
4.1.1. Leukemic Bone Marrow Niche
4.1.2. Lymphomagenesis and Tumor Microenvironment
4.1.3. The Tumor Microenvironment in Multiple Myeloma
5. Hypoxia and Tumor Microenvironment
6. Exosome in Tumor Microenvironment
6.1. Exosome Biogenesis
6.2. Exosomes in Leukemia
6.2.1. Exosomes in Chronic Myeloid Leukemia (CML)
6.2.2. Exosomes in Acute Lymphoblastic Leukemia (ALL)
6.2.3. Exosomes in Acute Myeloid Leukemia (AML)
6.3. Exosomes in Lymphomas
6.4. Exosomes in Multiple Myeloma (MM)
7. Exosome and miRNA Regulation in DR
7.1. Exosomal miRNA: Biogenesis
7.2. Exosomal miRNA: Mechanism and Action in Solid Tumor
7.2.1. Alteration of Drug Efflux Pump
7.2.2. Increased Resistance to Apoptotic Stimuli
7.2.3. Modulation of the Tumor Microenvironment
7.3. Exosomal miRNA in Hematological Tumor
7.3.1. miRNA and Leukemia: Chronic Myeloid Leukemia (CML)
Acute Myeloid Leukemia (AML)
Chronic Lymphocytic Leukemia (CLL)
7.3.2. Exosomal miRNA and Lymphoma
7.3.3. Exosomal miRNA and Multiple Myeloma (MM)
8. Conclusion and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ABCA3 | ATP Binding Cassette Subfamily A Member 3 |
ABC | ATP-binding cassette |
ALL | Acute lymphoblastic leukemia |
AML | Acute myeloid leukemia |
ADCC | antibody-dependent cell-mediated cytotoxicity |
ADME | absorption, distribution, metabolism and elimination |
ALIX | apoptosis linked gene 2 |
BCL9 | B-cell lymphoma 9 |
BIM | B-cell lymphoma-2 [BCL-2]–interacting mediator of cell death |
BM | bone marrow |
BMME | bone marrow microenvironment |
BMSCs | bone marrow stromal cells |
Btz | bortezomib |
CAECs | cancer-associated endothelial cells |
CAFs | cancer-associated fibroblasts |
CAV1 | Caveolin 1 |
CFU | colony forming unit |
CLL | Chronic lymphocytic leukemia |
CML | Chronic myeloid leukemia |
CNS | central nervous system |
CSC | cancer stem cells |
DLBCL | diffuse large B-cell lymphoma |
DR | drug resistance |
ECM | extracellular matrix |
EMT | epithelium-mesenchyme transition |
ESCRT | endosomal sorting complexes required for transport |
EVs | extracellular vesicles |
FDCs | Follicular dendritic cells |
GR | glucocorticoid receptor |
GTPases | guanosine triphosphase |
HCC | hepatocellular carcinoma |
HDAC6 | histone deacetylase 6 |
HL | Hodgkin’s lymphoma |
hnRNPA2B1 | Heterogeneous Nuclear Ribonucleoproteins A2/B1 |
HSCs | hematopoietic stem cells |
HUVECs | human vascular endothelial cells |
ICAM-1 | intercellular adhesion molecule-1 |
IL | interleukin |
ILV | intraluminal vesicles |
IM | imatinib |
IVs | intracellular vesicles |
LAM | lymphoma-associated macrophages |
lncRNAs | long non-coding RNAs |
LSCs | leukemic stem cells |
MAPK | MAP kinases |
MDR | multiple-DR |
MGUS | Monoclonal Gammopathy of Indeterminate Significance |
miRNA | micro-RNA |
MM | Multiple myeloma |
MMP | matrix metalloproteinase |
MSC | mesenchymal stem/stromal cells |
mTOR | mechanistic target of rapamycin |
mRNA | messenger RNA |
MSCs | mesenchymal stem cells |
MVBs | multivesicular bodies |
NF-kB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NHL | non-Hodgkin’s lymphoma |
NK | natural killer |
OPG | degrading osteoprotegerin |
OXPHOS | oxidative phosphorylation |
PARP | ADP-ribose polymerase |
PCs | plasmacells |
P-gp | p-glycoprotein |
Ph | Philadelphia chromosome |
PI | proteasome inhibitor |
PI3K | PhosphatidylInositol 3-Kinase |
PKM2 | Pyruvate Kinase M2 |
PTEN | Phosphatase and tensin homolog |
RS | Reed Sternberg cell |
SF | soluble factors |
SPHK2 | Sphingosine-1-phosphate, sphingosine kinase 2 |
SMART-exos | Synthetic Multivalent Antibodies ReTargeted Exosomes |
SNARE | the soluble N-ethylmaleimide-sensitive factor attachment protein receptor |
TAFs | Tumor-associated fibroblasts |
TAMs | tumor-associated macrophages |
TASCs | Tumor-associated stromal cells |
TGFβ1 | Transforming growth factor beta 1 |
Th | helper T cells |
TFH | follicular helper T cells |
TKIs | tyrosine kinase inhibitors |
TME | Tumor microenvironment |
Treg | regulatory T cells |
VEGF | Vascular-Endothelial Growth Factor |
VCAM-1 | vascular cell adhesion molecule-1 |
VTA1 | vesicle trafficking |
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Hematological Tumor | miRNA | Drug Resistance | Cell Type | Pathway | Ref. |
---|---|---|---|---|---|
Chronic myeloid leukemia (CML) | miR-1228 miR-1246 miR-1308 miR-149 miR-455-3p miR-365 miR-27a miR-451 miR-21 | Imatinib Imatinib Imatinib Imatinib Imatinib Imatinib Resistance phenotype Resistance phenotype Resistance phenotype | CEM CEM CEM CEM CEM CML CML CML CML | Exosome increaseExosome increase Exosome increase Exosome increase Exosome increase Bax-Caspase3 P-gp P-gp P-gp | [169] [169] [169] [169] [169] [170] [171] [171] [171] |
Acute myeloid leukemia (AML) | miR-7977 miR-19b miR-20a | Anthracyclines Anthracyclines Anthracyclines | HL-60/AR HL-60/AR HL-60/AR | P-gp PTEN and P-gp PTEN and P-gp | [172] [173] [173] |
Chronic lymphocytic leukemia (CLL) | miR-146a | Resistance phenotype | CCL | Akt-NF-kB | [173] |
Lymphoma | miR-181a miR-548m miR-99a-5p miR-125b-5p | Resistance phenotype Resistance phenotype Resistance phenotype Resistance phenotype | NHL NHL DLBCL DLBCL | Bim c-Myc-HDAC6 Exosome increase Exosome increase | [174] [175] [176] [176] |
Multiple myeloma | miR-627-3p miR-642a-5p miR-16-5p miR-15a-5p miR-20a-5p miR17-5 miR-30 | Bortezomib Bortezomib Bortezomib Bortezomib Bortezomib Bortezomib Resistance phenotype | LP-1 myeloma cells LP-1 myeloma cells U-226 myeloma cell U-226 myeloma cell U-226 myeloma cell U-226 myeloma cell H929 myeloma cell | SP9-PI3K/Akt SP9-PI3K/Akt Exosome increase Exosome increase Exosome increase Exosome increase BCL9-Wnt | [40] [40] [43] [43] [43] [43] [177] |
Type of Action | Name | Mechanism | Ref. |
---|---|---|---|
Exosome increase | miR-1228, miR-1246, miR-1308, miR-149, miR-455-3p | More abundant in the exosomes of ALL cell line | [169] |
miR-99a-5p, miR-125b-5p | Higher in exosomes from serum of chemo-resistant patients | [176] | |
Drug resistance | miR-365 | Inhibiting expression of pro-apoptosis proteins BAX and Cleaved Caspase-3 in CML cells | [170] |
miR-27a, miR-451, miR-21 | Increasing expression of P-gp | [171] | |
miR-7977 | Increasing expression of P-gp | [172] | |
miR-19b, miR-20a | Targeting PTEN and decreasing activation of PI3K/Akt signaling pathway | [173] | |
miR-146a | Activating Akt pathway and NF-kB in CLL | [173] | |
miR-181a | Protecting lymphoma cells from drug-induced apoptosis through BIM | [174] | |
miR-548m | Promoting c-Myc activation in lymphoma cells | [175] | |
miR-627-3p, miR-642a-5p | Targeting SP9 and activation of PI3K-Akt signaling pathway | [40] | |
miR-30 | Enhancing expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway | [177] | |
Exosomal biomarker | miR-15a-5p, miR-20a-5p, miR-17-5, miR-16-5p | Downregulation in exosomes from patients resistant to Btz compared to patients sensitive to Btz | [43] |
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Cariello, M.; Squilla, A.; Piacente, M.; Venutolo, G.; Fasano, A. Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors. Molecules 2023, 28, 116. https://doi.org/10.3390/molecules28010116
Cariello M, Squilla A, Piacente M, Venutolo G, Fasano A. Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors. Molecules. 2023; 28(1):116. https://doi.org/10.3390/molecules28010116
Chicago/Turabian StyleCariello, Mariaconcetta, Angela Squilla, Martina Piacente, Giorgia Venutolo, and Alessio Fasano. 2023. "Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors" Molecules 28, no. 1: 116. https://doi.org/10.3390/molecules28010116