Molecular Mechanisms of Endothelial to Mesenchymal Transition (EndMT)

Introduction

Endothelial to Mesenchymal Transition (EndMT) is a process characterized by the transformation of endothelial cells into mesenchymal cells. This transition is accompanied by the loss of endothelial markers and the upregulation of mesenchymal markers. EndMT plays a crucial role in various physiological and pathological processes, including embryonic development, tissue repair, organ fibrosis, cardiovascular disease, and cancer progression.ref.148.5 ref.148.5 ref.23.2 The molecular mechanisms underlying EndMT involve the activation of transcription factors and epigenetic modifications. In addition, environmental factors and signaling pathways play a significant role in regulating the induction and progression of EndMT. This essay will discuss the molecular mechanisms, environmental factors, signaling pathways, and involvement of non-coding RNAs in the regulation of EndMT.ref.148.5 ref.148.5 ref.23.2

Molecular Mechanisms of EndMT

The molecular mechanisms of EndMT involve the activation of transcription factors and epigenetic modifications. EndMT is characterized by the loss of endothelial markers, such as VE-Cadherin and CD31, and the upregulation of mesenchymal markers, including alpha-smooth muscle actin (α-SMA) and vimentin. These changes in gene expression are driven by various environmental factors, including high glucose, hypoxia, oxidative stress, pro-inflammatory cytokines, and disturbed shear stress.ref.148.5 ref.72.7 ref.72.7

Transcription factors such as SNAIL, SLUG, TWIST, ZEB1, and ZEB2 are upregulated during EndMT and play a crucial role in regulating the expression of endothelial and mesenchymal markers. These transcription factors bind to specific DNA sequences in the promoter regions of target genes, leading to their activation or repression. In addition to transcription factors, epigenetic modifications, including DNA promoter methylation, histone modifications, and non-coding RNAs, also play a role in regulating EndMT.ref.23.20 ref.72.7 ref.23.20

Epigenetic modifications can influence gene transcription by altering the accessibility of DNA to transcription factors and other regulatory proteins. DNA promoter methylation, which involves the addition of a methyl group to cytosine residues, can lead to gene silencing. Histone modifications, such as acetylation, methylation, phosphorylation, and ubiquitination, can affect chromatin structure and gene expression.ref.29.27 ref.33.3 ref.33.3 Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, can regulate gene expression by binding to messenger RNAs and either inhibiting their translation or promoting their degradation.ref.29.27 ref.29.27 ref.33.3

Environmental Factors and Signaling Pathways in EndMT

Environmental factors and signaling pathways play a significant role in regulating the induction and progression of EndMT. Under pathological conditions, factors such as high glucose, hypoxia, oxidative stress, pro-inflammatory cytokines, and disturbed shear stress can induce EndMT. These factors trigger the activation of signaling pathways, including the canonical Transforming Growth Factor Beta (TGF-β) pathway and non-canonical pathways such as Notch and Wnt.ref.7.5 ref.90.10 ref.90.10

The TGF-β pathway is one of the major signaling pathways involved in the regulation of EndMT. TGF-β ligands bind to their receptors, leading to the activation of downstream signaling cascades. This results in the activation of transcription factors, such as SMAD proteins, which regulate the expression of target genes involved in EndMT.ref.90.11 ref.90.11 ref.90.11 Notch signaling pathway activation has also been shown to induce EndMT. Notch ligands bind to Notch receptors, leading to the release of the Notch intracellular domain (NICD), which translocates to the nucleus and regulates gene expression. The Wnt pathway, another important signaling pathway, can also induce EndMT.ref.90.11 ref.90.11 ref.23.5 Wnt ligands bind to their receptors, leading to the activation of downstream signaling cascades and the regulation of target genes involved in EndMT.ref.90.11 ref.90.11 ref.23.5

In addition to these pathways, fibroblast growth factor (FGF) and mitogen-activated protein kinase (MAPK) pathways can modulate EndMT as inhibitory pathways. These pathways can counteract the effects of the TGF-β, Notch, and Wnt pathways and prevent the induction of EndMT. However, the specific mechanisms by which these pathways modulate EndMT are still being investigated.ref.90.10 ref.90.10 ref.90.10

Inflammatory Mediators and Immune Cells in EndMT

Inflammatory mediators and immune cells play a significant role in the progression of EndMT. Long-term exposure to inflammatory cytokines can induce EndMT by changing the morphology of endothelial cells and activating TGF-β signaling and other pathways. Inflammatory cytokines, such as high glucose, hypoxia, oxidative stress, and pro-inflammatory cytokines, trigger the activation of signaling pathways that induce EndMT.ref.148.5 ref.72.7 ref.72.7

Reactive oxygen species (ROS) induce NF-kB signaling, leading to inflammation and the accumulation of lipids, which contribute to the development of atherosclerosis. In addition, hyperglycemia enhances TGF-β signaling, which directly induces the progression of EndMT. The process of EndMT is gradual and multistep, and it can be reversible up to a certain point.ref.148.5 ref.148.5 ref.22.9 In summary, inflammatory mediators and immune cells contribute to the progression of EndMT by inducing morphological changes in endothelial cells and activating signaling pathways that lead to the acquisition of a mesenchymal phenotype.ref.148.5 ref.148.5 ref.23.9

Adhesion Molecules in EndMT

Adhesion molecules play a crucial role in the progression of EndMT. VE-Cadherin, CD31, and vascular endothelial cadherin (VE-cadherin) are endothelial markers that are downregulated during EndMT. These adhesion molecules are involved in maintaining the integrity and function of endothelial cells.ref.148.5 ref.92.12 ref.137.19 The downregulation of these adhesion molecules during EndMT contributes to the morphological changes and acquisition of mesenchymal characteristics by endothelial cells.ref.148.5 ref.92.12 ref.137.19

Non-coding RNAs in the Regulation of EndMT

Several specific microRNAs and non-coding RNAs have been found to play a role in regulating EndMT. These non-coding RNAs include miR-23, miR-126, miR-21, miR-302c, miR-18a, miR-20a, miR-29, miR-148b, miR-483, miR-31, miR-200b, miR-222, GATA6-AS, HECTD1, and circRNADLGAP4. These non-coding RNAs have been found to modulate the EndMT process during development and in various pathological conditions, including diabetes, cardiovascular disease, and fibrosis.ref.23.30 ref.23.12 ref.23.15

These non-coding RNAs can inhibit or facilitate EndMT by regulating the expression of endothelial and mesenchymal markers, as well as signaling pathways such as TGF-β, Wnt, and Notch. For example, miR-126 has been shown to inhibit EndMT by targeting the expression of SNAIL and ZEB1, two transcription factors involved in EndMT. On the other hand, miR-21 has been found to promote EndMT by targeting the expression of TGF-β receptor II, a key component of the TGF-β signaling pathway.ref.23.30 ref.23.12 ref.23.20

The specific functions and mechanisms of action of these non-coding RNAs may vary depending on the context and disease state. Further research is needed to fully understand the roles of these non-coding RNAs in EndMT and their potential as therapeutic targets for fibroproliferative diseases.ref.23.30 ref.23.30 ref.43.0

Conclusion

Endothelial to Mesenchymal Transition (EndMT) is a complex process regulated by various molecular mechanisms, environmental factors, signaling pathways, and non-coding RNAs. The activation of transcription factors and epigenetic modifications contribute to the induction of EndMT. Environmental factors such as high glucose, hypoxia, oxidative stress, pro-inflammatory cytokines, and disturbed shear stress, as well as signaling pathways including the TGF-β, Notch, and Wnt pathways, play a significant role in regulating the induction and progression of EndMT.ref.148.5 ref.148.5 ref.23.2 Inflammatory mediators and immune cells contribute to the progression of EndMT by inducing morphological changes in endothelial cells and activating signaling pathways. Adhesion molecules are downregulated during EndMT, contributing to the acquisition of mesenchymal characteristics by endothelial cells. Non-coding RNAs, including microRNAs and long non-coding RNAs, regulate the expression of endothelial and mesenchymal markers and signaling pathways involved in EndMT.ref.148.5 ref.148.5 ref.23.2 Further research is needed to fully understand the molecular mechanisms and potential therapeutic targets of EndMT for the prevention and treatment of fibroproliferative diseases.ref.148.5 ref.148.5 ref.90.8

Physiological Roles of Endothelial to Mesenchymal Transition

Introduction to Endothelial to Mesenchymal Transition (EndMT)

Endothelial to Mesenchymal Transition (EndMT) is a dynamic process in which endothelial cells lose their typical endothelial cell markers and functions and acquire a mesenchymal-like phenotype. This transition plays a critical role in tissue remodeling during development and wound healing. EndMT is required for the development of cardiac valves, the pulmonary and dorsal aorta, and arterial maturation during embryonic development.ref.137.3 ref.137.3 ref.137.3 It is also involved in physiological angiogenic sprouting and vessel growth. However, dysregulation of EndMT can contribute to various pathological conditions, including organ fibrosis, cardiovascular disease, and cancer progression.ref.137.3 ref.137.3 ref.137.3

Physiological Contexts of Endothelial to Mesenchymal Transition (EndMT)

A. Development During embryonic development, EndMT is necessary for the formation of cardiac valves, the pulmonary and dorsal aorta, and arterial maturation. It is also involved in embryonic pulmonary artery development and the formation of the smooth muscle component of the dorsal aorta.ref.72.8 ref.72.12 ref.72.8 EndMT is closely regulated by various signaling pathways and transcription factors, including VEGF, NOTCH, and Snail and Slug.ref.72.8 ref.72.8 ref.72.12

In physiological angiogenic sprouting and vessel development, EndMT is suggested to play a pivotal role. It has been shown that a partial EndMT process is necessary for the physiological process of angiogenic sprouting. The regulation of EndMT in this context involves various signaling pathways and transcription factors, including VEGF, NOTCH, and Snail and Slug.ref.141.24 ref.23.5 ref.72.8

Pathological Contexts of Endothelial to Mesenchymal Transition (EndMT)

A. Inflammatory conditions Under pathological pro-inflammatory conditions associated with high TGF-β2 levels, EndMT can occur. This suggests that EndMT plays a role in the immune response and inflammation.ref.148.5 ref.74.27 ref.74.27 The canonical TGF-β pathway, as well as non-canonical pathways such as Notch and Wnt, are involved in the induction of EndMT.ref.74.27 ref.148.5 ref.74.27

EndMT is implicated in organ fibrosis, including pulmonary fibrosis and myocardial fibrosis. The activation of EndMT in fibrotic conditions leads to the loss of endothelial markers and the upregulation of mesenchymal markers. The regulation of EndMT in fibrosis involves various signaling pathways and transcription factors, including TGF-β, Notch, and Wnt.ref.74.27 ref.72.12 ref.72.12

EndMT is observed in tumors and is suggested to contribute to cancer progression. The activation of EndMT in cancer cells promotes their invasive and migratory potential. The specific markers and signaling pathways associated with EndMT in the context of cancer may vary depending on the type of tumor.ref.148.5 ref.137.19 ref.156.3

EndMT is implicated in the pathogenesis of pulmonary hypertension. The activation of EndMT in pulmonary endothelial cells contributes to the remodeling of pulmonary vessels and the development of pulmonary hypertension. The regulation of EndMT in this context involves various signaling pathways, including TGF-β, Notch, and Wnt.ref.72.8 ref.72.8 ref.72.8

EndMT is believed to contribute to the development of atherosclerosis. Factors such as high low-density lipoprotein (LDL) cholesterol, a pro-inflammatory state, and disturbed flow patterns can induce EndMT in endothelial cells, leading to the progression of atherosclerosis. The regulation of EndMT in atherosclerosis involves various signaling pathways and transcription factors, including TGF-β, Notch, and Wnt.ref.148.5 ref.72.8 ref.72.8

Molecular Mechanisms and Markers of Endothelial to Mesenchymal Transition (EndMT)

A. Molecular mechanisms The regulation of EndMT is complex and involves various signaling pathways and transcription factors. The canonical TGF-β pathway is a key regulator of EndMT, and its activation leads to the loss of endothelial markers and the upregulation of mesenchymal markers.ref.148.5 ref.23.5 ref.148.5 Non-canonical pathways such as Notch and Wnt also play a role in the induction of EndMT. Inflammatory cytokines, high glucose, hypoxia, oxidative stress, and disturbed shear stress can induce EndMT and activate these signaling pathways.ref.148.5 ref.23.5 ref.148.5

EndMT is characterized by the loss of endothelial markers such as VE-Cadherin and CD31, and the upregulation of EndMT transcription factors SNAIL, SLUG, TWIST, ZEB1, and ZEB2, as well as mesenchymal markers such as α-SMA (ACTA2) and S100A4. The specific markers associated with EndMT may vary depending on the tissue and the specific disease context.ref.148.5 ref.72.7 ref.137.19

Conclusion

Endothelial to Mesenchymal Transition (EndMT) is a critical process that plays a role in tissue development and repair. It is required for the development of cardiac valves, the pulmonary and dorsal aorta, and arterial maturation during embryonic development. EndMT is also involved in physiological angiogenic sprouting and vessel growth.ref.137.3 ref.137.3 ref.137.3 However, dysregulation of EndMT can contribute to various pathological conditions, including organ fibrosis, cardiovascular disease, and cancer progression. The molecular mechanisms and markers of EndMT are complex and involve various signaling pathways and transcription factors. Further research is needed to fully understand the role of EndMT in different physiological and pathological contexts and to develop targeted therapies for diseases associated with EndMT dysregulation.ref.137.3 ref.137.3 ref.137.3

Pathological Roles of Endothelial to Mesenchymal Transition in Human Diseases

Endothelial to Mesenchymal Transition (EndMT) and its Role in Fibrotic Diseases

Endothelial to Mesenchymal Transition (EndMT) is a process that contributes to the progression of fibrosis in various organs. It involves the conversion of endothelial cells into mesenchymal or myofibroblastic cells, leading to the accumulation of fibroblasts and excess deposition of extracellular matrix (ECM). This transition has been observed in cardiac, renal, and pulmonary fibrosis, as well as in cancer invasiveness.ref.90.8 ref.2.4 ref.90.8 The regulation of EndMT is mediated by signaling pathways involving cytokines such as transforming growth factor (TGF)-β.ref.2.4 ref.90.8 ref.90.8

The phenotypic changes associated with EndMT include the loss of endothelial cell markers and the acquisition of a mesenchymal or myofibroblastic phenotype. This is characterized by the expression of markers such as α-smooth muscle actin (α-SMA), vimentin, and type I collagen. EndMT has been implicated in the development of various fibrotic diseases, including chronic kidney disease, portal venopathy, neointima formation in vein graft tissues, heterotopic ossification, intestinal fibrosis, radiation-induced rectal fibrosis, and fibrosis in multiple organs.ref.148.5 ref.148.5 ref.90.8

In the context of systemic sclerosis (SSc)-associated interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), there is ongoing debate regarding the role of EndMT. While it has been suggested to play a role in these conditions, the contribution of endothelial cells to the cardiac fibroblast population is limited.ref.74.4 ref.74.4 ref.3.3

The molecular mechanisms underlying EndMT involve the activation of signaling pathways mediated by cytokines such as TGF-β, integrin-linked kinase (ILK), and Wnt/β-catenin. These pathways are critical not only in the process of EndMT but also in the production of ECM proteins, which contribute to fibrosis. TGF-β1, in particular, plays a crucial role in tissue fibrosis and is involved in the generation of myofibroblasts through EndMT.ref.74.27 ref.138.3 ref.138.3 The TGF-β pathway is regulated by several transcriptional regulators, including Snail1, Snail2, Twist, and Zeb family proteins.ref.90.10 ref.74.27 ref.90.10

Further research is needed to fully understand the contribution of EndMT to fibrotic diseases in humans. However, the current understanding of the molecular mechanisms involved in EndMT provides insights into potential therapeutic targets for these conditions. The signaling pathways involved in EndMT, such as the TGF-β/Smad, ILK, and Wnt/β-catenin pathways, could serve as potential targets for therapeutic interventions in fibrotic diseases.ref.74.27 ref.74.27 ref.72.16

EndMT in the Pathogenesis of Atherosclerosis and Cancer Progression

EndMT is implicated in the pathogenesis of atherosclerosis, a chronic inflammatory disease characterized by the accumulation of plaque in arterial walls. In the context of diabetes, hyperglycemic damage to the macrovasculature triggers EndMT, leading to signaling derangement, generation of reactive oxygen species, and inflammatory cytokines. The mesenchymal cells derived from EndMT play a critical role in the progression of atherosclerosis by secreting proinflammatory signaling molecules and producing ECM proteins that contribute to plaque formation.ref.148.5 ref.22.23 ref.148.5 Therefore, targeting EndMT could be a potential therapeutic strategy for diabetic macrovascular complications and atherosclerosis.ref.22.23 ref.22.23 ref.148.5

EndMT is also involved in cancer progression, where it contributes to the conversion of endothelial cells into mesenchymal-lineage cell types, particularly myofibroblasts. This aberrant EndMT leads to the acquisition of a mesenchymal phenotype by endothelial cells, which promotes disease progression. In various pathological conditions, including cancer, EndMT is characterized by the downregulation of endothelial markers and the upregulation of mesenchymal markers.ref.148.5 ref.141.24 ref.72.7 The constitutive propensity of endothelial cells undergoing EndMT in tumors contributes to their mesenchymal transition.ref.148.5 ref.141.24 ref.72.7

EndMT as a Potential Therapeutic Target for Human Diseases

Targeting EndMT has emerged as a potential therapeutic strategy for various human diseases. In diabetic cardiomyopathy, further investigations into the extent of epigenetic modifications in EndMT could lead to better therapies for diabetic complications. Atherosclerosis, the macrovascular complication of diabetes, is thought to arise from chronic inflammation and injury to arterial walls, leading to the accumulation of plaque.ref.22.23 ref.22.23 ref.22.19 Targeting EndMT could be a promising approach to prevent or slow down the progression of atherosclerosis. In systemic sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension, the role of EndMT is still a topic of debate. However, understanding the molecular mechanisms underlying EndMT in these conditions could provide insights into potential therapeutic targets.ref.22.23 ref.22.19 ref.22.19

In addition to the aforementioned diseases, EndMT has been implicated in the pathogenesis of other conditions, such as cancer progression and canine myxomatous mitral valve disease. In cancer, targeting EndMT could potentially inhibit the conversion of endothelial cells into mesenchymal-lineage cell types, which contribute to disease progression. In canine myxomatous mitral valve disease, targeting developmental mechanisms, including EndMT, could potentially lead to therapeutic interventions.ref.72.8 ref.127.1 ref.148.5

In conclusion, EndMT plays a significant role in the pathogenesis of various human diseases, including fibrotic diseases, atherosclerosis, cancer progression, systemic sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension, and canine myxomatous mitral valve disease. The understanding of the molecular mechanisms underlying EndMT in different diseases can provide insights into potential therapeutic targets for these conditions. Targeting EndMT could be a promising approach for the development of novel therapies to prevent or treat these diseases.ref.127.20 ref.72.8 ref.72.12 However, further research is needed to fully elucidate the contribution of EndMT to fibrotic diseases and other pathological conditions in humans.ref.127.20 ref.72.8 ref.72.12

Endothelial to Mesenchymal Transition and Cancer Progression

Introduction

The phenomenon of Endothelial to Mesenchymal Transition (EndMT) and its role in cancer progression is discussed in the provided document excerpts. EndMT is a process in which endothelial cells lose their typical endothelial characteristics and acquire a mesenchymal-like phenotype. This transition is characterized by the downregulation of endothelial markers such as CD31, VE-Cadherin, and von Willebrand factor, and the upregulation of mesenchymal markers such as α-SMA and vimentin.ref.148.5 ref.72.7 ref.141.24 Inflammatory cytokines and TGF-β signaling are known to induce EndMT. EndMT has been implicated in various pathologies, including cancer progression. The acquisition of invasive and migratory properties by mesenchymal cells derived from EndMT contributes to the metastatic properties of cancer cells.ref.148.5 ref.72.7 ref.141.24 However, the specific mechanisms by which EndMT contributes to the acquisition of invasive and metastatic properties in cancer cells are not explicitly discussed in the provided document excerpts.ref.148.5 ref.72.7 ref.148.5

Specific Cancer Types Relevant to EndMT

There are several specific cancer types in which EndMT is particularly relevant. These include non-small cell lung carcinoma (NSCL), malignant melanoma, and breast cancer. EndMT has been implicated in cancer progression and is characterized by the loss of endothelial markers and the upregulation of mesenchymal markers.ref.148.5 ref.141.23 ref.148.5 It is believed that the dysregulation of angiogenic signaling pathways can cause an imbalance in endothelial physiology, leading to EndMT. The induction of EndMT in cancer cells and endothelial cells co-cultured with cancer cells has been observed in the context of TGF-β1 signaling. Additionally, inflammatory cytokines can induce EndMT and contribute to disease progression, including cancer.ref.141.24 ref.148.5 ref.141.23 It is important to note that the involvement of EMT-related transcription factors in EndMT has also been suggested. Overall, the specific cancer types in which EndMT is particularly relevant are non-small cell lung carcinoma, malignant melanoma, and breast cancer.ref.72.7 ref.72.7 ref.148.5

Regulation of EndMT in Cancer Cells

The process of EndMT in cancer cells is regulated through various mechanisms. One of the factors that can induce EndMT is long-term exposure to inflammatory cytokines, which can change the morphology of endothelial cells and ignite signaling pathways such as TGF-β. Inflammatory cytokines can also shift the expression of endothelial markers towards mesenchymal markers, leading to increased cell migration.ref.148.5 ref.141.24 ref.156.3 Dysregulation of angiogenic signaling pathways can also cause an imbalance in endothelial physiology, leading to EndMT in cancer progression. Additionally, EMT-related transcription factors, such as SNAIL, SLUG, TWIST, ZEB1, and ZEB2, are involved in the regulation of EndMT. It has been observed that endothelial cells can induce EMT in breast epithelial cells with stem cell properties, suggesting a role for endothelial cells in the regulation of EMT.ref.141.24 ref.156.3 ref.148.5 Furthermore, endothelial cells have been shown to induce EMT in lung epithelial cells and can mediate proliferative and morphogenic signals to breast epithelial cells. EndMT has been implicated in cancer progression, including breast cancer, and is associated with the acquisition of a mesenchymal phenotype and cancer stem cell properties. The regulation of EndMT in cancer cells involves various factors and pathways, including inflammatory cytokines, angiogenic signaling, and EMT-related transcription factors.ref.148.5 ref.156.1 ref.72.7

Key Factors Promoting EndMT in Cancer Progression

The key factors involved in promoting EndMT during cancer progression include long-term exposure to inflammatory cytokines, which can induce EndMT by changing the morphology of endothelial cells and activating TGF-β signaling and other pathways. EndMT is characterized by the loss of endothelial markers such as CD31, CD34, VE-cadherin, and von Willebrand factor, and the upregulation of mesenchymal cell markers such as α-SMA and vimentin. Inflammatory cytokines, such as TNF-α, can also induce EMT in tumor cells and EndMT in endothelial cells co-cultured with cancer cells.ref.148.5 ref.156.3 ref.141.24 Other factors that can induce EMT and potentially contribute to EndMT include transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), and components of the extracellular matrix. Dysregulation of angiogenic signaling pathways, such as VEGF and TGF-β, can cause an imbalance in endothelial physiology and contribute to EndMT during cancer progression. Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, also play a role in modulating EndMT during development and disease.ref.156.3 ref.141.24 ref.156.3 The process of EndMT is gradual, reversible up to a certain point, and occurs in various pathologic conditions, including cancer progression.ref.72.7 ref.148.5 ref.141.24

Downstream Signaling Pathways in EndMT during Cancer Progression

The downstream signaling pathways activated during EndMT in cancer progression include the TGF-β signaling pathway, inflammatory cytokine signaling pathways, Wnt/b-catenin pathway, and FGF signaling pathway. These pathways are involved in the induction of EndMT and the regulation of EMT-related transcription factors, leading to the acquisition of a mesenchymal phenotype by endothelial cells. The activation of these pathways results in the downregulation of endothelial markers and the upregulation of mesenchymal markers, promoting cell migration and invasion.ref.148.5 ref.141.24 ref.72.7 Additionally, the NF-κB pathway and non-coding RNAs have also been implicated in the regulation of EndMT. These findings suggest that dysregulation of angiogenic signaling pathways and inflammatory activation can contribute to the progression of cancer through the induction of EndMT.ref.141.24 ref.148.5 ref.72.7

Biomarkers and Molecular Signatures Associated with EndMT in Cancer

Yes, there are biomarkers and molecular signatures associated with EndMT in cancer. EndMT is characterized by the loss of endothelial markers such as VE-Cadherin and CD31, and the upregulation of EndMT transcription factors SNAIL, SLUG, TWIST, ZEB1, and ZEB2, as well as mesenchymal markers such as α-SMA and S100A4. Inflammatory cytokines can induce EndMT by changing the morphology of endothelial cells and altering the expression of endothelial and mesenchymal markers.ref.148.5 ref.137.19 ref.141.23 Dysregulation of angiogenic signaling pathways can cause an imbalance in endothelial physiology, leading to EndMT in cancer progression. EndMT is involved in various pathologies, including cancer progression, and contributes to disease progression by promoting the transformation of endothelial cells into mesenchymal-lineage cell types. However, specific biomarkers or molecular signatures associated with EndMT in cancer were not mentioned in the provided document excerpts.ref.141.24 ref.148.5 ref.141.23

Targeting EndMT Pathways as a Potential Therapeutic Approach for Cancer Treatment

Targeting EndMT pathways can be a potential therapeutic approach for cancer treatment. Dysregulation of angiogenic signaling pathways can lead to an imbalance in endothelial physiology, resulting in EndMT, which has been implicated in cancer progression. Combination therapies that involve the use of immune checkpoint inhibitors and anti-angiogenic agents have shown enhanced cytotoxic activity and a normalizing effect on tumor vasculature.ref.141.24 ref.141.23 ref.141.12 However, it is important to note that anti-angiogenic therapies, including normalizing therapies, may induce the transformation of tumor-associated endothelial cells towards a mesenchymal profile, known as EndMT. EndMT can support the formation of cancer-associated fibroblasts, facilitate tumor progression, and modify the endothelium abnormally, assisting tumor-cell extravasation. Additionally, EndMT can be triggered by the reduction in the expression of ERG and FLI1 transcription factors, leading to the downregulation of endothelial genes and the upregulation of genes involved in EndMT.ref.141.23 ref.141.24 ref.148.5 Therefore, targeting EndMT pathways may be a promising approach for cancer treatment.ref.141.12 ref.157.20 ref.141.24

Experimental Models and Techniques to Study Endothelial to Mesenchymal Transition

Introduction

Endothelial to Mesenchymal Transition (EndMT) is a process in which endothelial cells lose their typical endothelial cell markers and adopt a mesenchymal-like phenotype. It plays a crucial role in various developmental processes and pathologies, including organ fibrosis, cardiovascular disease, and cancer. Studying EndMT is important for understanding the underlying mechanisms and developing effective strategies to manipulate this process.ref.148.5 ref.137.3 ref.137.3 In this essay, we will explore the commonly used in vitro models to study EndMT, the genetic and pharmacological approaches used to manipulate EndMT in experimental models, and the limitations and challenges in studying EndMT.ref.148.5 ref.137.3 ref.148.5

In vitro models to study EndMT

1. Induction of EndMT by inflammatory cytokines Long-term exposure to inflammatory cytokines can induce EndMT by changing the morphology of endothelial cells and upregulating mesenchymal markers. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) have been shown to induce EndMT in vitro.ref.148.5 ref.92.12 ref.92.21 This model allows researchers to investigate the role of inflammation in promoting EndMT and its implications in various diseases.ref.92.21 ref.92.12 ref.92.12

2. Induction of EndMT by environmental factors Under pathological conditions, various environmental factors such as high glucose, hypoxia, oxidative stress, pro-inflammatory cytokines, and disturbed shear stress can induce EndMT. For example, high glucose levels, commonly seen in diabetes, can induce EndMT in endothelial cells.ref.148.5 ref.22.23 ref.148.5 This model allows researchers to study the effects of specific environmental factors on EndMT and understand the mechanisms involved.ref.22.23 ref.148.5 ref.148.5

3. Activation of signaling pathways EndMT can be induced by signaling pathways such as the canonical Transforming Growth Factor Beta (TGF-b) pathway or non-canonical pathways like Notch and Wnt. For example, TGF-β signaling has been shown to play a crucial role in promoting EndMT.ref.148.5 ref.23.5 ref.148.5 Activation of TGF-β pathway leads to the upregulation of mesenchymal markers and downregulation of endothelial markers. This model allows researchers to investigate the specific signaling pathways involved in EndMT and their downstream effects.ref.148.5 ref.23.5 ref.148.5

4. Co-culture models Co-culturing endothelial cells with other cell types, such as cancer cells, can induce EndMT and provide insights into the role of EndMT in cancer progression. For example, co-culture of endothelial cells with breast cancer cells has been shown to induce EndMT and promote tumor invasion and metastasis.ref.148.5 ref.141.23 ref.72.7 This model allows researchers to study the crosstalk between endothelial cells and other cell types and understand the factors that promote EndMT in a tumor microenvironment.ref.141.23 ref.141.23 ref.148.5

5. Animal models Animal models can be used to study EndMT, although they may not fully represent the pathophysiology of human diseases. However, research from animal models can provide useful reference information.ref.92.24 ref.72.8 ref.148.5 For example, transgenic mouse models with targeted gene deletions or overexpressions can be used to investigate the role of specific genes or signaling pathways in EndMT. These models allow researchers to study the in vivo effects of manipulating EndMT and validate findings from in vitro studies.ref.92.24 ref.148.5 ref.72.8

Genetic and pharmacological approaches to manipulate EndMT

Genetic and pharmacological approaches can be used to manipulate EndMT in experimental models. These approaches involve targeting specific genes, signaling pathways, or factors involved in EndMT to either induce or inhibit the process. The choice of approach depends on the specific research question and the experimental model being used.ref.23.12 ref.23.5 ref.22.5

1. Genetic approaches Researchers have studied the role of various signaling pathways and transcription factors in regulating EndMT. For example, the Transforming Growth Factor Beta (TGF-b) pathway, Notch pathway, and Wnt pathway have been implicated in inducing EndMT.ref.90.10 ref.7.5 ref.7.5 On the other hand, fibroblast growth factor (FGF) and mitogen-activated protein kinase (MAPK) pathways have been shown to inhibit EndMT. Genetic approaches involve the manipulation of these pathways or transcription factors using techniques such as gene knockout or overexpression. For example, knockout of the TGF-β receptor in endothelial cells can prevent EndMT induction.ref.90.10 ref.7.5 ref.90.10 These approaches allow researchers to investigate the specific genes and pathways involved in EndMT and their functional implications.ref.7.5 ref.7.5 ref.90.10

2. Pharmacological approaches Pharmacological approaches involve the use of drugs or compounds to target specific signaling pathways or factors involved in EndMT. For example, inhibitors of the TGF-β pathway or activators of inhibitory pathways like FGF or MAPK could be used to manipulate EndMT in experimental models.ref.75.27 ref.7.5 ref.7.5 These compounds can be administered to cells or animals to modulate the activity of specific pathways and observe the effects on EndMT. Pharmacological approaches offer the advantage of being able to target multiple pathways simultaneously and allow for more precise control over the timing and duration of manipulation.ref.75.27 ref.75.27 ref.7.5

It is important to note that the specific genetic and pharmacological approaches used to manipulate EndMT may vary depending on the experimental model and the specific research question being addressed. Further research is needed to fully understand the mechanisms underlying EndMT and to develop effective strategies for manipulating this process in experimental models.ref.92.24 ref.23.5 ref.92.24

Limitations and challenges in studying EndMT

1. Complexity of the process EndMT is a complex process that involves multiple signaling pathways and regulatory factors. The molecular mechanisms and regulatory factors involved in EndMT are not fully understood.ref.72.8 ref.23.5 ref.72.8 Further research is needed to identify the specific factors that promote or inhibit EndMT and understand their interactions. Additionally, EndMT is a reversible process, and the factors that determine the reversibility of EndMT and the mechanisms involved are still poorly understood.ref.72.8 ref.23.5 ref.72.8

2. Lack of standardized experimental models There is a need for better experimental models that accurately mimic the in vivo conditions and allow for the study of EndMT in a controlled environment. Currently, there is a lack of standardized protocols for inducing or quantifying EndMT, which makes it difficult to compare results from different studies.ref.92.24 ref.72.8 ref.148.5 The use of different cell types, culture conditions, and markers for defining EndMT further complicates the interpretation of results. It is important to develop standardized protocols and criteria for defining and quantifying EndMT to ensure reproducibility and comparability of results.ref.72.8 ref.148.5 ref.92.24

3. Role of non-coding RNAs Non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, have been found to modulate EndMT during development and disease. These non-coding RNAs can regulate the expression of genes involved in EndMT and play a role in its regulation.ref.23.30 ref.23.30 ref.23.30 However, the specific non-coding RNAs involved and their mechanisms of action are still not fully understood. Further research is needed to identify the specific non-coding RNAs that modulate EndMT and understand their functional implications.ref.23.30 ref.23.30 ref.23.30

4. Epigenetic modifications Epigenetic modifications, such as DNA methylation patterns, have also been implicated in EndMT. These modifications can regulate the expression of genes involved in EndMT and determine the fate of endothelial cells.ref.148.5 ref.137.18 ref.137.18 However, the extent and functional implications of these modifications require further investigation. Understanding the role of epigenetic modifications in EndMT can provide insights into the long-term stability and reversibility of this process.ref.137.18 ref.148.5 ref.137.18

In conclusion, studying EndMT presents challenges in terms of experimental models, molecular mechanisms, and regulatory factors. The commonly used in vitro models to study EndMT include induction by inflammatory cytokines, environmental factors, activation of signaling pathways, co-culture models, and animal models. Genetic and pharmacological approaches can be used to manipulate EndMT in experimental models, targeting specific genes, signaling pathways, or factors involved in EndMT.ref.148.5 ref.92.24 ref.72.7 The available techniques to quantify and visualize EndMT in tissues and cells include the analysis of endothelial and mesenchymal markers, immunofluorescence staining, flow cytometry, RNA analysis, live-cell imaging, and transgenic animal models. However, there are limitations and challenges in studying EndMT, including the complexity of the process, lack of standardized experimental models, role of non-coding RNAs, and epigenetic modifications. Further research is needed to fully understand the mechanisms underlying EndMT and develop effective strategies for manipulating this process in experimental models.ref.148.5 ref.72.7 ref.72.7

Works Cited