Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles
Abstract
:1. Introduction
2. Cancer-Derived EVs Transform Normal Cells into Cancer Cells
3. Cancer-Derived EVs Transform Cancer Cells into Cancer Stem Cells
3.1. Support for Cancer Stem Cell Niche by EVs
3.2. EMT-Mediated Transformation of Non-CSCs into CSCs
3.3. Role of EV piRNAs in Transformation of Non-CSCs into CSCs
3.4. Role of Other EV Cargoes in the Transformation of Non-CSCs into CSCs
4. Cancer-Derived EVs Transform Stromal Microenvironment Cells into Cancer-Associated Support Cells
4.1. Transformation of Fibroblasts into Cancer-Associated Fibroblasts (CAFs)
4.2. Transformation of Nerve Cells into Cancer-Associated Nerve Cells
4.3. Transformation of Immune Cells into Cancer-Associated Types
4.4. Cancer-Derived EVs for Transformation of Other Cell Types
5. Therapeutic Applications of EVs Involved in TME Modulation
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Type | Morphological Characteristics | Pathophysiological Characteristics | Molecular Profile | Reference |
---|---|---|---|---|
Cancer-associated fibroblasts (CAFs) | Loss of fusiform form | -High secretion of ECM components -Tumor progression | αSMA, FAP, vimentin, and PDGFRα | [12,13] |
Tumor-associated macrophages (TAMs) | Often elongated morphology, increase in size | -Immunosuppressive activity -Tumor progression | M2-type polarization CD163, CD206, Arg1, and IL10 | [14,15] |
Tumor-associated neutrophils (TANs) | Not defined | -Immunosuppressive activity -Tumor progression | Overexpression of chemokines CCL2, CCL3, CCL4, CCL8, CCL12, CCL17, CXCL1, CXCL2, IL-8/CXCL8, and CXCL16 | [16,17] |
Tumor-infiltrated/-associated natural killer cells (TINKs/TANKs) | Not defined | -Immunosuppressive activity --Tumor progression | CD56bright, overexpressed NKG2A, and lower levels of KIRs and LILRB1 | [18,19] |
Tumor-infiltrated/-associated dendritic cells (TIDCs/TADCs) | Form tertiary lymphoid structures (TLSs) | -Immunosuppressive activity -Tumor progression -Do not present tumor-derived antigens | Not defined | [20,21] |
Tumor endothelial cells (TECs) | Irregular surfaces, excessively fenestrated cell walls, loose intercellular junctions to adjacent cells | Tumor progression | Aneuploidy, VEGF autocrine loop, responsiveness to EGF, and adrenomedullin | [22,23] |
Cancer-associated adipocytes (CAAs) | Elongated form, loss of a considerable number of lipid droplets | Tumor progression | Overexpressed CCL5 and CCL2, increased production of the pro-inflammatory cytokines IL-6 and TNF-α | [24,25] |
Cancer-associated keratinocytes (CAKs) | Not defined | Tumor progression | DMBT1 suppression | [26] |
Cell type without certain phenotype | ||||
Nerve cells | Increase in axonal network | Tumor progression | Overexpressed Eph | [27,28] |
Pericytes | Loss of integrity with the blood vessel | Tumor progression | Pericyte–fibroblast transition (PFT) | [25] |
T lymphocytes | Form tertiary lymphoid structures (TLSs) | Secretion of pro-inflammatory cytokines and chemokines | Not defined | [29] |
B lymphocytes | Form tertiary lymphoid structures (TLSs) | Secretion of immunosuppressive cytokines and antibodies | Secretion of IL-10, TGFb, and IgA | [30,31] |
Lymphatic endothelial cells (LECs) | Recruit myeloid lymphatic endothelial cell progenitors (M-LECPs) from bone marrow for lymphoangiogenesis | Tumor progression | LYVE1 and podoplanin | [32] |
Hallmark of Transformed Cancer Cell | Cancer-Derived EV Factors | Mechanism of Action | Reference |
---|---|---|---|
Sustaining proliferative signaling | H-ras and K-ras transcripts; miR-125b, miR-130b, and miR-155; Ras superfamily of GTPases Rab1a, Rab1b, and Rab11a | Genetic instability, MET, and oncogenic transformation | [66] |
Evading growth suppressors | circRNA_100284 | Inhibition of EZH2/cyclin-D1 gene silencing | [55] |
hsa_circ_0000069 | Enhance the expression of the STIL gene | [56] | |
Avoiding immune destruction | exosomal regulating proteins and miRNAs PD-1, MET, RAF1, BCL2, and mTOR | PD-1 overexpression | [67] |
Enabling replicative immortality | hTERT transcript | Translated into a full-fledged enzyme and initiates telomere elongation | [68] |
Tumor-promoting inflammation | Not defined | Increasing transcription of genes for inflammation-supporting cytokines and chemokines (IL-6, IL-8 IL-1, and CXCL-8) | [69] |
Activating invasion and metastasis | hsa_circ_0000069 | Enhance the expression of the STIL gene | [56] |
ANXA1 | Not defined | [62] | |
Inducing or accessing vasculature | TIE2 | High expression of VEGF, PDGF-bb, IL-10, IL-6, IL-1β, and TNFα | [70] |
miRNA-21 | Activation of PDK1/AKT signaling. Secretion of VEGF, MMP2, MMP9, bFGF, and TGF-β | [53] | |
Genome instability and mutation | Not defined | Exosomes induce random genetic change | [37,64] |
Resisting cell death | miR-224-5p | Inhibition of the oncosuppressor—CMTM4 | [61] |
Deregulating cellular metabolism | miR-105 | Activates the MYC pathway, enhances glycolysis, glutamine decomposition, and detoxifies the metabolites (lactate and NH4+) | [71,72] |
Unlocking phenotypic plasticity | ΔNp73 | Induction of proliferation potential and chemoresistance | [73] |
Nonmutational epigenetic reprogramming | SND1-IT1 | Competitively absorb miR-1245b-5p Recruit DDX54 to upregulate USP3 expression SNAIL1 deubiquitination | [58] |
Polymorphic microbiomes | Not defined | Not defined | _ |
Senescent cells | Not defined | Not defined | _ |
Cells of TME | Tumor Cells EV Factors | Consequence | Reference |
---|---|---|---|
Cancer-associated fibroblasts (CAFs) | Piwil2-iCSC | Increase in the expressions of MMP2 and MMP9 | [114] |
Gm26809 | Not defined | [115] | |
miR-146a | Downregulation of the TXNIP gene, activation of the Wnt signaling pathway | [116] | |
miR-27a | Directly target the oncosuppressor CSRP2, induction of the ERK and PAK/LIMK/cortactin signaling cascades | [117,118] | |
hTERT | Enhancement of telomerase activity | [119] | |
Upregulations of αSMA and vimentin | [68] | ||
Tumor-associated macrophages (TAMs) | miR-103a | Decrease in PTEN levels, increased activation of AKT and STAT3 | [120] |
miR-29a-3p | Increase in the phosphorylation of STAT1 | [121] | |
miR-21 | Increase in expressions of IL-6 and TNF-α | [122] | |
Tumor-associated neutrophils (TANs) | KRAS | Upregulation of IL-8 production | [123] |
HMGB1 | Activation of the NF-κB pathway | [124] | |
circ-CTNNB1 | Increase in PD-L1 expression | [125] | |
Tumor-infiltrated/-associated natural killer cells (TINKs/TANKs) | TGF-β1 | Downregulations of activating receptors: NKG2D, NKP30, NKP44, NPK46, and NKG2C | [126] |
NKG2DL | Downregulation of NKG2D expression | [127] | |
miR-378a-3p | Decrease in granzyme-B (GZMB) secretion | [128] | |
Tumor endothelial cells (TECs) | Not defined | Inhibition of TRPV4 | [129] |
Cancer-associated adipocytes (CAAs) | miR-1304 | Regulation of GATA2 gene expression | [130] |
Target Cell | Cargo(es) | Outcomes | Cancer Type | Reference |
---|---|---|---|---|
Tumor cells | mir-302s | Reprogramming tumor cells into induced pluripotent stem cells with decreased tumorigenicity | Skin cancer | [226] |
Exosomes derived from human embryonic stem cells | Reprogramming tumor cells into induced pluripotent stem cells with decreased tumorigenicity | Mammary carcinoma, colorectal adenocarcinoma | [227] | |
CSC | Cell-derived exosomes with osteoinductive potential (OD-EXOs) | Reprogramming cancer stem cells into nontumorigenic cells Enhanced expression of osteogenic-related genes (alkaline phosphatase [ALPL], osteocalcin [BGLAP], and runt-related transcription factor 2 [RUNX2]) | Osteosarcoma | [228] |
TAM | Antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6) | Reprogramming TAMs toward pro-inflammatory M1 and generation of a CD8 T-cell-mediated adaptive immune response Selectively silences STAT6 expression in TAMs; induces nitric oxide synthase 2 (NOS2) | Colorectal cancer, hepatocellular carcinoma | [229] |
Exosomes derived from M1-type macrophages (M1-Exo) | Reprogramming of TAMs toward pro-inflammatory M1; increased phagocytic function and robust cross-presentation ability | Breast cancer, colon adenocarcinoma | [230] | |
Exosomes derived from bone marrow mesenchymal stem cell (BM-MSC), electroporation-loaded galectin-9 siRNA, and surficially modified oxaliplatin (OXA) | Reprogramming TAMs toward pro-inflammatory M1; cytotoxic T lymphocyte recruitment and Treg downregulation | Pancreatic ductal adenocarcinoma (PDAC) | [231] | |
CAF | Calcipotriol (ligand of vitamin D receptor) | Conversion of activated to quiescent pancreatic stellate cells (myofibroblast-like cells) Increased intratumoral gemcitabine delivery | Pancreatic tumors | [232] |
Dasatinib (PDGFR inhibitor) | Conversion of activated to quiescent fibroblasts | Lung adenocarcinomas | [159] |
Tumor Type | Title of Drug | Phase of Clinical Trials | Short Described | Result | NCT Number |
---|---|---|---|---|---|
Pancreatic cancer | iExosomes | 1 | Mesenchymal stromal cell-derived exosomes with KrasG12D siRNA | - | NCT03608631 |
Hepatocellular carcinoma | exoASO-STAT6 (CDK-004) | 1 | Delivery of the STAT6 antisense oligonucleotide (ASO) to the myeloid to repolarize macrophages from immune-suppressive M2 to the proinflammatory M1 phenotype | - | NCT05375604 |
Lung cancer | CSET 1437 | 2 | Immunotherapy involving metronomic cyclophosphamide (mCTX) followed by vaccinations with tumor antigen-loaded dendritic-cell-derived exosomes (Dexs). mCTX inhibits Treg functions restoring T and NK cell effector functions and Dexs are able to activate the innate and adaptive immunity | - | NCT01159288 |
Head and neck cancer | - | 1 | Grape exosomes to reduce the incidence of oral mucositis during radiation and chemotherapy treatments | - | NCT01668849 |
Acute myeloid leukemia | UCMSC-Exo | 1 | Umbilical-cord-derived mesenchymal stem cells exosomes (UCMSC-Exos) for effectively promoting recovery of myelosuppression | - | NCT06245746 |
Bladder cancer | - | Early Phase 1 | Chimeric exosome vaccine based on dendritic cells or macrophages secretion | - | NCT05559177 |
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Ten, A.; Kumeiko, V.; Farniev, V.; Gao, H.; Shevtsov, M. Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles. Cells 2024, 13, 682. https://doi.org/10.3390/cells13080682
Ten A, Kumeiko V, Farniev V, Gao H, Shevtsov M. Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles. Cells. 2024; 13(8):682. https://doi.org/10.3390/cells13080682
Chicago/Turabian StyleTen, Artem, Vadim Kumeiko, Vladislav Farniev, Huile Gao, and Maxim Shevtsov. 2024. "Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles" Cells 13, no. 8: 682. https://doi.org/10.3390/cells13080682