Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression
Abstract
:1. Introduction
2. Molecular Mechanisms of EMT
2.1. Key Molecular Markers and Phenotypic Changes Associated with EMT
2.2. Role of Transcription Factors (e.g., SNAIL, TWIST, ZEB) in Regulating EMT
2.3. Signaling Pathways Implicated in EMT Induction (e.g., TGF-β, Wnt/β-catenin, Notch)
3. Microenvironmental Factors Influencing EMT
3.1. Stromal Cells and Their Paracrine Signaling
3.2. Extracellular Matrix Components
3.3. Hypoxia and Metabolic Alterations in EMT
3.4. Metabolic Alterations
3.4.1. Glucose Metabolism
3.4.2. Lipid Metabolism
3.4.3. Amino Acid Metabolism
3.4.4. Nucleic Acids Metabolism
3.5. Inflammatory Cytokines and Growth Factors Promoting EMT Induction
3.5.1. Inflammatory Cytokines
3.5.2. TNF-α
3.5.3. IL-1β
3.5.4. IL-6
3.5.5. IL-8
3.6. Growth Factors
4. Epigenetic Regulation of EMT
4.1. DNA Methylation and Histone Modifications Affecting EMT-Related Gene Expression
4.2. Chromatin Remodeling Complexes and Their Role in EMT Plasticity
4.3. Non-Coding RNAs (miRNAs, lncRNAs) as Regulators of EMT Signaling
5. Cellular Plasticity and EMT
5.1. Hybrid Epithelial/Mesenchymal States and Their Relevance in Cancer Progression
5.2. Phenotypic Switching between Epithelial and Mesenchymal State
5.3. Plasticity-Driven Drug Resistance and Implications for Therapy
6. Experimental Models for Studying EMT
6.1. In Vitro Models (Cell Culture, Organoids) to Investigate EMT Mechanisms
6.2. In Vivo Models for Studying EMT in Tumor Progression and Metastasis
6.3. Advances in Imaging and Single-Cell Technologies for Dissecting EMT Dynamics
6.4. Predicting Critical Transitions in EMT: From Biomarkers to Advanced Mathematical Models
7. Clinical Implications of EMT
7.1. Prognostic Significance of EMT Markers in Cancer Patients
7.2. Targeting EMT for Therapeutic Intervention
7.3. Challenges and Opportunities in Translating EMT [Table 1]
Challenges | |
---|---|
Complexity of EMT | EMT involves intricate molecular mechanisms and signaling pathways, making it difficult to pinpoint specific targets for therapeutic intervention [6] |
Biomarker identification | A challenge in identifying universal biomarkers is the heterogeneity of EMT across cancer types and within individual tumours [6]. |
Therapeutic resistance | EMT resistance spans chemotherapy, radiotherapy, and more, impeding treatment efficacy at various levels. Common mechanisms of drug resistance include enhanced drug efflux and evasion of apoptosis or necrosis. For instance, SLUG and SNAIL can thwart treatment-triggered apoptosis by disrupting p53 function or suppressing the tumor-suppressor PTEN [2]. |
Limited clinical validation | Numerous EMT-targeted therapies showing promise in preclinical studies await thorough clinical validation [8]. |
Adverse effects of anti-EMT treatment | Anti-EMT treatment may have the opposite effect than originally expected. Because EMT plays very important physiological roles, targeting EMT not only affects tumour-cell subpopulations but can also have a negative impact on normal cells [20]. |
8. Future Directions and Challenges
8.1. Identification of Novel Regulators and Therapeutic Targets for EMT Inhibition
8.2. Integration of Multi-Omics Data for a Comprehensive Understanding of EMT Dynamics
8.3. Development of Innovative Therapeutic Strategies to Target EMT-Associated Processes
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
α-SMA | Smooth muscle actin |
ACC | Acetyl-CoA carboxylase |
Asn | Asparagine |
ASNS | Asparagine synthetase |
BC | Breast cancer |
BFAL1 | Bacteroides fragilis lncRNA1 |
BRAFi | B-Raf Protein Kinase Inhibitors |
CAAs | Cancer-associated adipocytes |
CAFs | Cancer-associated fibroblasts |
ccRCC | Clear cell renal carcinoma |
COLI | Collagen-I |
COLIV | Collagen-IV |
CSCs | Cancer stem cells |
CtBP | C-terminal Binding Protein |
D6PD | 6-Phosphogluconate Dehydrogenase |
DATS | Diallyl trisulfide |
DDR | Discoidin domain receptor |
DDR2 | Discoidin domain receptor 2 |
dNTPs | Deoxyribonucleoside triphosphates |
EGF | Epidermal growth factor |
EGFRs | Surface receptors for EGF |
EMP | E/M plasticity |
EMT | Epithelial-mesenchymal transition |
ENAH | Enabled Homolog |
ERK1/2 | Extracellular signal–regulated kinase1 and 2 |
ERRα | Estrogen-related receptor α |
ESRP | Epithelial splicing regulatory protein |
Evs | Extracellular vesicles |
EZH2 | Enhancer of Zeste Homolog 2 |
FAK | Focal adhesion kinase |
FASN | Fatty acid synthase |
FBP1 | Fructose-1,6-bisphosphatase 1 |
FGF | Fibroblast growth factor |
FGFR2IIIc | Epithelial-Type IIIb isoform to the mesenchymal-like IIIc isoform |
FGFRs | FGF receptors |
Gln | Glutamine |
GRHL2 | Grainyhead-like 2 |
GLS1 | Glutaminase 1 |
GSH | Glutathione |
H3K27ac | Histone H3 acetylated at lysine 27 |
H3K4Me3 | H3 lysine 4 trimethylation |
H3K36Me3 | H3 lysine 36 trimethylation |
HCC | Hepatocellular carcinoma |
HDACs | Histone Deacetylases |
HIFs | Hypoxia-inducible factors |
HGF | Hepatocyte growth factor |
HNSCC | Head-and-neck squamous cell carcinoma |
HREs | Hypoxia response elements |
iCAF | Inflammatory cancer-associated fibroblasts |
Ig | Immunoglobulin |
IGF-1R | Insulin-like growth factor-1R |
IKK | IκB kinase |
iNOS | Induced nitric oxide synthase |
JMJD3 | Lysine (K)-specific demethylase 6B |
JNK | Jun N-terminal kinase |
lncRNAs | Long non-coding RNAs |
LOCKs | Large Organized Chromatin K9-modified Domains |
LOX | Lysyl oxidase |
LUAD | Lung adenocarcinoma |
LZTR1 | Leucine zipper-like transcriptional regulator 1 |
MALAT1 | Metastasis-associated lung adenocarcinoma transcript 1 |
MAPKi | MAP Kinase Inhibitors |
Mbd3/NuRD | Methyl CpG-binding domain/3 Mi-2/nucleosome remodeling and deacetylase complex |
MCP-1 | Monocyte chemoattractant protein-1 |
MDSCs | Myeloid-derived suppressor cells |
MET | Mesenchymal-epithelial transition |
myCAFs | Myofibroblastic cancer-associated fibroblasts |
NF-κB | Nuclear factor κ-light-chain-enhancer of activated B cells |
NICD | NOTCH intracellular domain |
OPG | Osteoprotegerin |
OS | Overall survival |
PAAD | Pancreatic ductal adenocarcinoma |
PC | Prostate cancer |
PFS | Progression-free survival |
PKA | Protein kinase A |
POSTN | Periostin |
pO2 | Oxygen partial pressure |
PPP | Pentose phosphate pathway |
PRC2 | Polycomb Repressive Complex 2 |
PTX3 | Long pentraxin-3 |
pVHL | Von Hippel-Lindau protein |
PyM | Pyrimidine metabolism |
ROS | Reactive oxygen species |
SCD | Stearoyl-CoA desatuRase |
SGOC | Serine/glycine one-carbon |
SNHG15 | Small nucleolar RNA host gene 15 |
SPARC | Secreted protein acidic and rich in cysteine |
SRSF1 | Serine/arginine-rich Splicing Factor 1 protein |
SSP | Serine synthesis pathway |
SUZ12 | Suppressor of Zeste 12 |
TACE | TNF-α converting enzyme |
TAK1 | Transforming growth factor-activating kinase 1 |
TCF2 | Transcription factor 2 |
TGFβ | Transforming growth factor β |
TME | Tumor microenvironment |
TMEM | Microenvironment metastasis |
TNF-α | Tumor necrosis factor α |
UPR | Unfolded Protein Response |
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Tomecka, P.; Kunachowicz, D.; Górczyńska, J.; Gebuza, M.; Kuźnicki, J.; Skinderowicz, K.; Choromańska, A. Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression. Int. J. Mol. Sci. 2024, 25, 8972. https://doi.org/10.3390/ijms25168972
Tomecka P, Kunachowicz D, Górczyńska J, Gebuza M, Kuźnicki J, Skinderowicz K, Choromańska A. Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression. International Journal of Molecular Sciences. 2024; 25(16):8972. https://doi.org/10.3390/ijms25168972
Chicago/Turabian StyleTomecka, Paulina, Dominika Kunachowicz, Julia Górczyńska, Michał Gebuza, Jacek Kuźnicki, Katarzyna Skinderowicz, and Anna Choromańska. 2024. "Factors Determining Epithelial-Mesenchymal Transition in Cancer Progression" International Journal of Molecular Sciences 25, no. 16: 8972. https://doi.org/10.3390/ijms25168972