Center for Global Health Research, Saveetha Medical College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
Rush University Medical Center, Chicago, Illinois, USA
Correspondence
Nanasaheb Thorat, Limerick Digital Cancer Research Centre and Department of Physics, Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Limerick V94T9PX, Ireland.
Limerick Digital Cancer Research Centre and Department of Physics, Bernal Institute, University of Limerick, Castletroy, Limerick, Ireland
Correspondence
Nanasaheb Thorat, Limerick Digital Cancer Research Centre and Department of Physics, Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Limerick V94T9PX, Ireland.
Center for Global Health Research, Saveetha Medical College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
Rush University Medical Center, Chicago, Illinois, USA
Correspondence
Nanasaheb Thorat, Limerick Digital Cancer Research Centre and Department of Physics, Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Limerick V94T9PX, Ireland.
Limerick Digital Cancer Research Centre and Department of Physics, Bernal Institute, University of Limerick, Castletroy, Limerick, Ireland
Correspondence
Nanasaheb Thorat, Limerick Digital Cancer Research Centre and Department of Physics, Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Limerick V94T9PX, Ireland.
Nobendu Mukerjee, Sagnik Nag and Bikramjit Bhattacharya contributed equally to this work.
Abstract
The epithelial–mesenchymal transition (EMT) represents a pivotal frontier in oncology, playing a central role in the metastatic cascade of cancer—a leading global health challenge. This comprehensive review delves into the complexities of EMT, a process where cancer cells gain exceptional mobility, facilitating their invasion into distant organs and the establishment of secondary malignancies. We thoroughly examine the myriad of factors influencing EMT, encompassing transcription factors, signalling pathways, metabolic alterations, microRNAs, long non-coding RNAs, epigenetic changes, exosomal interactions and the intricate dynamics of the tumour microenvironment. Particularly, the review emphasises the advanced stages of EMT, crucial for the development of highly aggressive cancer phenotypes. During this phase, cancer cells penetrate the vascular barrier and exploit the bloodstream to propagate life-threatening metastases through the mesenchymal–epithelial transition. We also explore EMT's significant role in fostering tumour dormancy, senescence, the emergence of cancer stem cells and the formidable challenge of therapeutic resistance. Our review transcends a mere inventory of EMT-inducing elements; it critically assesses the current state of EMT-focused clinical trials, revealing both the hurdles and significant breakthroughs. Highlighting the potential of EMT research, we project its transformative impact on the future of cancer therapy. This exploration is aimed at paving the way towards an era of effectively managing this relentless disease, positioning EMT at the forefront of innovative cancer research strategies.
1 INTRODUCTION
Cancer can be defined as the uncontrolled proliferation/growth of cells leading to many complications. According to the worldwide scenario, cancer can be considered as the second leading cause of death in humanity.1 The hallmark of cancer conceptualisation is a heuristic method to reduce the vast complexity of cancer phenotypes and genotypes to a tentative set of guiding principles. Other aspects of the disease have emerged as potential improvements as our understanding of the processes behind cancer has increased.2 As our understanding of the processes underlying cancer has deepened, additional facets of the disease have emerged as potential avenues for improvement. Efforts to decipher the molecular and genetic intricacies of cancer have paved the way for targeted therapies and personalised medicine. The identification of specific molecular markers associated with different cancer types has enabled the development of tailored treatment approaches, improving outcomes for many patients. Cancer metastatic spread and treatment resistance are both influenced by the epithelial-to-mesenchymal transition (EMT), a process in which epithelial cells develop mesenchymal phenotypic characteristics.3 When epithelial cells undergo classic EMT, as initially observed during embryonic development, they transform into cells with a mesenchymal phenotype identified by archetypal markers such as E-cadherin and vimentin. This process is essential for several developmental stages of the embryo.4 Some transcription factors (TFs) (TWIST, ZEB and SNAIL) play a crucial role in EMT. EMT-TFs play a crucial role in all stages of cancer development, from initiation through primary tumourigenesis, invasion, spread and metastasis to resistance to therapeutic approaches.4 A cobblestone-shaped epithelial cell gradually acquires a dilated appearance during this process.5 Activation of different signalling pathways such as Wnt, Hedgehog and Notch leads to EMT.6 Early distributed tumour cells that have become quiescent may have undergone an EMT transition state that tends to develop more mesenchymal cells and severity of tumour cells that cause their quiescence. Snail is one of the EMT-TFs associated with reducing the rate of cellular proliferation. Furthermore, by attaching to the flanking region of the proliferating nuclear antigen gene, Snail could inhibit tumour cell proliferation and decrease their expression.7 In EMT, the exosome is a new concept; generally, it is a subpopulation of extracellular vesicles (EVs). It is associated with cellular communication, but tumour-derived exosomes (TEXs) influence EMT in carcinogenesis.8 MicroRNAs (miRNAs) are linked to EMT in a more complicated way.9 EMT is one of the greatest challenges in the development of advanced cancer therapeutics.7 In this comprehensive review, we meticulously explore a spectrum of factors influencing the regulation of EMT in cancer. Our analysis encompasses a diverse range of regulatory elements, including TFs, signalling pathways, metabolic regulations, miRNAs, long non-coding RNAs (lncRNAs), epigenetic modifications and the role of exosomes in EMT dynamics. Acknowledging the complexities of EMT research, this review delves into the challenges inherent in the field, not to mention, tumour heterogeneity, dynamic cellular plasticity and the evolving understanding of EMT across different cancer types are discussed, adding a layer of realism to the narrative and prompting a thoughtful consideration of the hurdles that researchers may encounter. EMT research history is summarised in Figure 1. Unlike conventional reviews, this article goes beyond a cursory examination of therapeutic strategies and offers a holistic perspective on the various therapeutic approaches targeting EMT along with clinical evidence. By critically assessing the current therapeutic landscape, the review provides insights into potential theranostic avenues for impeding cancer progression and metastasis.
Journey of epithelial–mesenchymal transition (EMT) research. Reproduced with permission under Creative Commons CC by 4.0 license from Ref. 331 Copyright @ 2022 The Authors.
2 ROLE OF TRANSCRIPTION FACTORS IN EMT
The process of EMT is regulated by several signalling molecules. For example, gastrulation-related EMT is regulated by Wnt signalling. Neural crest formation associated with EMT initiated by transforming growth factor-beta (TGF-β), Wnt, BMP, Notch signalling molecule, etc. EMT type I is involved in organogenesis, type II EMT is induced by vascular endothelial growth factor (VEGF) and TGF-β and type III EMT has interrelationship with Wnt, TGF-β, vascular epithelium molecules growth factor, etc. Overall, this cluster of molecules (Sanil, Twist, Zeb) activated several signalling pathways and a group of TFs that play the main regulators in EMT.10 β-Catenin is involved in two different cell functions. One complements the cellular cytoskeleton and E-cadherin and is a vital molecule in Wnt signalling. Phosphorylation of β-catenin activated several downstream genes associated with EMT.11-13 Snail is one of the zinc finger proteins first classified from Drosophila melanogaster and is involved in mesoderm formation associated with gastrulation. The snail family protein is found in the fruit fly; however, it also occurs in the vertebrate. There are three snail family of proteins such as Snail1, Snail2 and Snail3. Scientific research suggests that suppression of E-cadherin promotes EMT in sea urchins. Several signalling pathways (Notch, epidermal growth factor [EGF], phosphoinositide 3-kinases (PI3K)–AKT, etc.) are associated with the activation of snails.14 Snail is one of the best-studied regulatory molecules of E-cadherin expression.15 E-cadherin is the trademark of EMT and its expression is regulated by Snail2 and Snail3.16 Snail protein modified cellular adhesion protein17, 18 and its higher expression promotes EMT. In addition, Snail is also involved in the modification of the cell matrix. In various snails, they affect the cell cycle, cancer cells survive and escape those involved except the EMT. It also affects the cell cycle and survival of cancer cells and evades apoptosis. As a result, it promotes the development of cancer stem cells (CSCs) such as the micro-population in cancer.19, 20 This scientific invention will be next validated when researchers get the higher expression of CD44 a (marker for CSCs).21, 22 Zinc finger E-box binding homeobox or ZEB is contracted by two homologous subunits ZEB1 and ZEB2.23 SNAIL1 is another vital TF affecting the E-cadherin promoter region.24 A recent finding suggests that ZEB enhances cancer metastasis by inhibiting E-cadherin expression.25 bHLH TFs maintain cell proliferation, differentiation and maintenance of the cell lineage during the developmental phase. It is interrelated with several TFs (TWIST1, TWIST2, TCF3, TCF4 and TCF12) that regulate EMT.26 TWIST1 suppresses E-catharine expression and promotes cancer metastasis.27 Molecular interactions such as Twist and SET8 alter the expression pattern of E-cadherin (low) and N-cadherin (high) and promote EMT.28 TF-related clinical studies show that thiolutin (THL), a PSMD14 inhibitor, suppresses the PSMD14/SNAIL axis and thus prevents metastatic and chemoresistant esophageal squamous cell carcinoma.29
3 ROLE OF SIGNALLING PATHWAYS ACTIVATION OF EMT
The EMT is a process in which tumour cells develop a cellular migration capability.30 In general, EMT (type I) embryogenesis and organ development, wound healing (EMT type II) and cancer metastasis (type III).31 Vital signalling pathways such as Wnt, Notch, TGF-β, Hedgehog, AKT/Mechanistic Target of Rapamycin (mTOR), Janus Kinases (JAK)/Signal Transducer and Activator of Transcription 3 (STAT3) and others have promoted EMT activation.32 Several TFs such as Twist, Smads and Snail connect these signalling pathways.33 Phosphorylation-mediated β-catenin mutation in Wnt signalling that impairs E-cadherin expression. Mutated β-catenin accumulates in the cell nucleus and acts as a transcription activator of the growth-promoting genes.34 Notch signalling pathway, EMT, triggered by Notch is restricted to cells expressing active Notch. This stimulation causes endothelial cells to synergistically upregulate Snail, implying that simultaneous expression of Slug and Snail is essential for EMT induction.33 TGF signalling pathway, Smads cause gene reprogramming that directly increases EMT-TFs. TGF-β also activates multiple signalling pathways such as MAP kinase (MAPK), mTOR and AKT.35 Hedgehog signalling pathway, namely Sonic Hedgehog (Shh), can activate EMT in carcinoma. The Hedgehog signalling pathway is actively involved in EMT-associated gene expression.36 AKT/mTOR signalling pathway, AKT regulates EMT by repressing the expression of E-cadherin via EMT-TFs. mTOR complexes control the EMT by regulating the cell's actin cytoskeleton through PKC phosphorylation, resulting in downstream activation of Akt.37 JAK/STAT3 signalling pathway STAT3 has been extensively studied in TFs related to EMT and cancer. Interleukin-6 (IL-6)-mediated JAK2/STAT3 activation promotes metastasis and increases cell motility (EMT-TFs—Snail and Twist).38 Signalling pathways are complex patterns of molecular connections that regulate EMT in cancer. This area requires further scientific research to establish innovative strategies for cancer treatment. Several clinical investigations revealed that signalling pathways target EMT-related therapeutic development. Cancer research has turned its attention to the development of therapeutics that inhibit the EMT process by interfering with various signalling pathways.37, 39 Scientific evidence suggests that bufarin, a bioactive polyhydroxysteroid derived from a Chinese herb, acts for the first time against ovarian epithelial cancer cells and primary ovarian tissue in a xenograft tumour model and patient specimens to inhibit growth and migration. Research confirmed that bufalin inhibits mTOR and lowers Hypoxia-Inducible Factor 1 (HIF-1). Bufalin inhibited ovarian cancer cell proliferation and migration by inhibiting both mTOR and HIF-1.40
4 ROLE OF METABOLIC REGULATION IN EMT
One of the hallmarks of tumour progression is metabolic reprogramming (Figure 2). Cancer cells modify cell metabolism in a variety of ways to gain energy and meet the need for expansion. The glucose metabolism of CSCs is at the heart of the primary metabolic study. Glycolysis or oxidative phosphorylation (OXPHOS) of CSCs depends on tumour origin and microenvironment.41 Compared to normal cells, cancer cells are more dependent on glycolysis (Warburg effect) to cover their increased energy expenditure during growth.42 EMT-associated high glycolysis events promote the development of CSCs.43-46 Aerobic glycolysis in cancer cells is associated with EMT.47 Anoikis is a type of cell death that occurs when the cell's matrix attachment is insufficient, resulting in excessive reactive oxygen species (ROS) that destroy the cell.48 EMT bypasses anoikis by reducing oxidative metabolism via the Warburg effect to reduce ROS generation.49 Some endocrine tumours have dysregulated glycolytic enzymes, although their involvement in EMT is uncertain. Pancreatic cancer cells upregulate glycolytic enzymes and glucose transporters.50 In endocrine malignancies such as thyroid, pancreatic and high-grade serous ovarian tumours, Glut1 is elevated and inhibits Glut1, stopping glycolysis-mediated cancer development.51, 52 Lactate dehydrogenase (LDH) (it is involved in the conversion of pyruvate to lactate) plays an important role in EMT.53 Experimental evidence shows that lower LDH expression slows down the rate of metastasis in gastric cancer.54 In blabber cancer, high levels of LDH lead to cancer metastasis and EMT.45 An in vivo study suggests that turning off LDH can control pancreatic cancer.55 Mitochondrial functional transformation is associated with EMT and metastasis.56 Downregulation of mitochondrial OXPHOS increases EMT and metastasis by altering mitochondrial DNA (mtDNA) levels.57 mtDNA mutation is involved in aggressive metastasis.58 Fumarate hydratase, which converts fumarate to malate, mutation of which is associated with pheochromocytoma and paraganglioma metastases. The high fumarate concentration leads to epigenetic and DNA hypermethylation, mitochondrial dysfunction and ROS production.59-63 This event, on the other hand, changes the function of α-ketoglutarate. As a result, it affects epigenetic modification that promotes metastasis and EMT.64 Many cancers are related to aerobic glycolysis as well as de novo lipogenesis. We have very little information on the correlation between lipid metabolism and cancer.65 Higher expression of acyl-CoA synthetases leads to fatty acids in acyl-CoA and stearoyl-CoA desaturase-1 (SCD), which promote EMT in colorectal cancer.66 The functional change of SCD is associated with breast cancer.67 According to scientific research, prostate cancer metastases can be prevented by inhibiting SCD.68 Metabolic pathways that change the pattern in EMT (which pose challenges for therapeutic development) could therefore reveal important therapeutic targets that are vulnerable. Kato et al. showed that simvastatin alters metabolism in ovarian cancer, except to inhibit the development of aggressive petals. This approach shows promising results in phase II clinical trials (trail IDs NCT03324425, NCT04985201) and in combination with other drugs in ovarian cancer.69 In triple-negative breast cancer pathway, targeting EMT inhibitors in the clinical trial (NCT03244358).70
Epithelial–mesenchymal transition (EMT) and metabolism interlink. Reproduced with permission under Creative Commons CC by 4.0 license from Ref. 332 Copyright @ 2020 The Authors.
5 ROLE OF miRNAs IN EMT
miRNAs are 20–22 nucleotide non-coding single-stranded RNAs. It is involved in post-transcriptional modification via the binding of 3′ untranslated regions of mRNAs.71 A single miRNA targets multiple mRNAs, and a single mRNA can regulate multiple miRNAs.72 Intracellular adhesion is regulated by E-cadherin.73 miRNA-9 is related to cell migration and overexpression of miRNA-9 is observed in breast cancer. β-Catenin signalling association and miRNA-9-based downregulation of E-cadherin lead to high expression of VEGR and promote cancer angiogenesis.74 Lung cancer EMTs regulate TGF signalling-mediated, miRNA-9-based lower expression of E-cadherin.75 miRNA-15b is associated with tongue cancer.76 Lung cancer EMT is regulated by miRNA-15b (inhiation Bcl2 apoptosis regulator protein)77 and is also associated with brain cancer EMT via the expression of MMP protein.78 miRNA-23a-mediated TGF signalling, E-cadherin downregulation has been implicated in lung EMT79 and is also implicated in kidney EMT.80 The association of miRNA-27 and Wnt signalling leads to gastric cancer EMT.81 In breast cancer, miRNA-27 plays a crucial role in tumour suppression gene alteration mediated by EMT.82 miRNA-29a-mediated tristetraproline (TTP) suppuration connection with Ras pathway-associated EMT.83 miRNA-29a-mediated reduced TTP expression and the higher expression of vimentin.83 miRNA-29b plays an important role in extracellular matrix (ECM) reprogramming.84 miRNA-30 enhances N-cadherin85 and miRNA-107 downregulates E-cadherin expression and promotes EMT.86 miRNA-1555p regulates the proliferation and invasion of cancer cells.87 miRNA-194 involves multiple complex signalling pathways and MMP protein expression as well as EMT.88, 89 miR-200 has a recent role in inhibiting EMT.90-94 In breast cancer, miRNA-221 and miRNA-222 are associated with EMT and metastasis.95-97 Several studies have shown that miRNAs can suppress EMT by targeting the TFs involved in Wnt signalling or its downstream targets. As a result, overexpression of these miRNAs can be a therapeutic technique to block EMT.98 Scientific evidence indicates that overexpression of miR498 significantly reduced the EMT pathway and thus inhibited migration, invasion and proliferation of liver cancer cells. In liver cancer cells, overexpression of miR-498 induces cancer cell death.54 In some cases, the downregulation of certain miRNAs is beneficial in inhibiting EMT signalling and cancer progression, as reported by Shan et al.40 They showed that downregulation of exosome miRNA 148b-3p develops chemoresistance in bladder cancer (higher expression of Phosphatase and Tensin Homolog (PTEN) and lower expression of β-catenin).40
6 ROLE OF LONG NON-CODING RNAs IN EMT
lncRNAs consist of 200 bases containing non-coding RNA.99 Current scientific studies indicate that lncRNAs play a role in the development of cancer. lncRNAs are regulated by several protein-coding genes.100 lncRNA-mediated EMT is initiated with TGF signalling.101 In liver cancer, ZEB1-AS1 and lncRNA-ATB reprogram the cancer cells, the combination of TGF signalling.102, 103 Breast cancer is influenced by the involvement of lncRNAs (lncRNA-HIT, lncRNA-HIT, treRNA) in TGF signalling and Wnt signalling; as a result, E-cadherin expression has decreased.101, 104 Metastasis-associated lung adenocarcinoma transcript (MALAT1) lncRNAs have a strong correlation in several cancer types (prostate, liver, lung, kidney and breast) via TGF signalling and lower expression of miRNA-205.105, 106 Hox Transcript Antisense Intergenic RNA (Hotair) lncRNAs are related to gene silencing107, 108 and involve the downregulation of miRNA-7, miRNA-34 and miRNA-141.109-113 Guo et al.114 report on the non-coding RNA-mediated nanotherapeutic against hepatocellular carcinoma. Folate-conjugated nanocarriers are used for delivery of miRNA-125 in an in vivo system demonstrating inhibition of liver cancer progression (metastasis and EMT) via inhibition of STAT3 protein and Wnt pathways.114
7 ROLE OF EPIGENETIC MODIFICATION IN EMT
EMT accelerates the cancer rate.115, 116 In addition, it is involved in the migration of cancer cells and the development of invasiveness properties.76 Some classified EMT-TFs coordinated this event.117 In the cellular system, a complicated epigenetic mechanism is related to gene expression.76, 118 In cancer, epigenetic modification (DNA methylation, acetylation, etc.) is indirectly linked to tumour development. Several epigenetic pathways, particularly histone alterations, can result in transcriptional reprogramming to control EMT and tumour growth.118 The histone protein's globular domains interact with DNA, and their N-terminal face is modified by several post-translational modifications (acetylation, methylation, etc.). Histone modifications determine the transcriptional expression of EMT-TFs (Twist, Snail, Zeb, etc.).115 Histone acetylation process in which an acetyl chemical group evolves a lysine-linked amino acid of the histone protein. This reaction affected the transcription process. DNA methylation is an intricate phenomenon where methyl groups are added to the CpG sequence, altering gene expression. Epigenetic changes in breast cancer are regulated by XEB2119 and Snail-mediated repression (involvement of histone-specific demethylase 1, LSD1 binding with CDH1 promoter) E-cadherin promotes EMT. Addition of a methyl group at the 5-position of cytosine results in transcriptional repression of chromatin. Recruitment of several methyl DNA binding domain (MBD) proteins such as MeCP2, MBD1–4 and Kaiso is required for DNA methylation-mediated transcription silencing.120, 121 Pancreatic cancer TWIST downregulates E-cadherin and promotes EMT.122 EMT is essential for cancer metastasis and chemoresistance, and understanding its dynamics is critical in designing effective therapies. A new promising method for EMT-related disorders appears to use epigenetic structure to prevent EMT in disease progression.123 Several enzymes related to epigenetics are now a target for therapeutic research (clinical trials for different malignancies).124 Histone deacetylase inhibitors (HDACi) prevent metastasis by upregulating genes that cause apoptosis while downregulating genes that promote motility, angiogenesis, EMT and cell survival. Several HDACi are FDA approved such as romodepsin, vorinostat (SAHA), panobinostat, belinostat, etc. used in various cancers and many others in different stages of the clinical trial.125
8 ROLE OF EXOSOMES IN EMT
Exosomes are subpopulations of EVs and originate from the endosomes. It facilitated the broad spectrum of intracellular communication related to cellular health and pathological conditions.126 In cancer, (Tumor-derived exosomes) TEXs carry several biologically active molecules that are implicated in the development of the aggressive metastatic nature of cancer.127 TEXs promote EMT (Figure 3). Exosomes released from cancer-associated fibroblasts (CAFs) carry TFs Snail that downregulates E-cadherin in A549 cells.128 In thyroid cancer, SLUG, and SOX2 regulate the high secretion of exosomes and enhance EMT.129 Exosomes form the bridge between tumour cells and the tumour microenvironment (TME). Research has shown that drug resistance to breast cancer-released exosomes promotes increased expression of HSPgp96, which degrades p53 and promotes EMT.130, 131 CAFs secreted exosomes of IL-6 cargo implicated in the development of aggressive bladder cancer.132 TEX's exosomal MAP17 cargo is associated with EMT.133 CAFs triggered the exosome SOD1-related cancer cell proliferation, EMT, metastasis and stem cell development in breast cancer.134 Most exciting is that the surface of exosomes expressing integrin protein (construct with and subunit) assists circulating cancer cells to migrate to specific organs (such as the lung, brain, bone, liver and lymph nodes).135-137 TEXs also regulate CSC-mediated therapeutic resistance development.138 Exosomal miRNAs are a group of 20–24 nucleotides containing non-coding RNA that affects multiple cellular events.139 In liver cancer exosome, miRNA-92a-3p downregulates the tumour suppressor gene PTEN and activates Akt and the cochlea pathway, enhancing EMT.140 In breast cancer exosomes, miRNA-181 regulates EMT.141 In colon cancer, exosome miRNA cargo (miRNA-934, miRNA-253p, miRNA-425-5p, miRNA-130b-3p) downregulates PTEN and enhances the subpopulation of macrophages 2 (M2) and enhances EMT.142, 143 Exosomes also carry another non-coding RNA, called lncRNAs, which carries 200 nucleotides and seeds tissue specificity.144 CAFs release exosomes carrying lncRNA RPPH1 and LINC00659 associated with colorectal cancer.145, 146 Thyroid CSCs derived from exosomal MALAT1–lncRNA promote EMT. Bladder cancer exosome lncRNA (LINC00960, LINC02470) unregulated Notch and catenin signalling pathways affect EMT.147 Exosomal cirRNAs are implicated in several cancer-associated events.148 In lung cancer, exosomal cirRNAs (circ-CPA4, circPTPRA, circFARSA) promote EMT.149-151 Exosomal circ_0001359 cirRNAs activated TGF signalling and enhanced EMT in pancreatic cancer.152 In gastric cancer, exosomal cirRNAs (circNRIP1) upregulated EMT-makers and accelerated metastatic events.148 A very interesting part of EMT is the remodelling of the ECM, and this event is also influenced by exosome cargo (fibronectin, etc.).127 Exosomes DNA cargo carries the signature of cancer mutation.153 In cancer, the exosome adds a new chapter. It has a great impact on the cancer theranostics research field and it is one step closer to cancer precision medicine.154-157 Exosome-based theranostic development journey faces exosome heterogeneity which is solved via a single exosome profiling method and exosome bercoding.158, 159 In future, exosomes may be a better solution for cancer treatment.
Epithelial–mesenchymal transition (EMT) and exosomes. Created with BioRender.com.
9 ROLE OF TUMOUR MICROENVIRONMENT IN EMT INITIATION
EMT is crucial for body development and tumour invasion. EMT develops tumour cell polarity and invasiveness through the remodelling of cellular matrix disruption.160 The TME in terms of cellular reprogramming amplifies EMT in cancer. In TME, inflammation promote cancer development.161 Hypoxia is a silent event involved in the development of CSCs.162 EMT initiation on tumour cells can be triggered by dynamic molecular cascades such as hypoxia, ROS, inflammation and cytokine.163 The E-cadherin expression of tumour and epithelial cells indicates a transition from mesenchyme to epithelium (MET).164 Infiltration of leukocytes, chemokines and cytokines is important in cancer-related inflammation.165 Tumour-associated macrophages and their secreted interferon-1 and tumour-necrosing factor-alpha (TNF-α) are involved in the development of aggressive metastatic phenomena.166 Oxidative stress and hypoxia in EMT lead to larger tumours when cancer cells divide uncontrollably. The resulting microenvironment has a restricted supply of metabolic raw materials during the hypoxic environment.167 Formation of ROS by mitochondria increases during hypoxia. ROS and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) have been shown to facilitate EMT when activated by TNF-α.168 EMT and stem cells recent research indicates that cells undergoing EMT may also have stem cell-like properties.169 Cancer cells exposed to hypoxia develop CSC-like properties and become resistant to conventional chemotherapy.170 MSCs are also present in the tumour stroma of many malignancies.162 EMT can be caused by several variables in the TME.171 The current knowledge of classical signalling pathways, together with new EMT principles, could accelerate cancer research and help elucidate the processes underlying EMT so that they can be used in a targeted manner.
10 EMT IN CANCER
EMT is interrelated in invagination, migration, plasticity and malignancy. Metastasis involves multiple events such as the formation of a secondary tumour, angiogenesis and quiescence. The remodelling of the ECM changes the morphology of the epithelial cells and as a result, the cells develop motility properties. During metastasis, when cells migrate to the secondary site of the removed organ, micrometastasis occurs from EMT to MET. Finally, secondary tumour formation occurs.172, 173 In renal injury reaping, BMP7 plays a vital role in MET promotion.174 EMT is regulated via TGF and non-conical Wnt signalling. TFG activated several factors associated with EMT and reduced anticancer cytotoxic T-lymphocyte activity.175 Twist1 and Twist2 TFs repress the tumour suppression gene (p53, Rb) and promote EMT.176 During EMT, cancer cells develop anoikis resistance and slowly develop chemoresistance.177 In the TME, CAFs release IF-, IF-1, IF-6 and HIF-1 to promote EMT. The RB1 controls E-cadherin expression and in EMT, downregulation of RB1 promotes mesenchymal marker expression and EMT occurs.178 This event is also related to the development of breast CSCs.179 Slug, Sox9 and Kruppel-like factor 8 TFs promote breast cancer (EMT).180, 181 Overdeclaration EGFR downregulates E-cadherin and β-catenin insists on EMT and cancer invasion.182 Zab1 is associated with highly aggressive cancer EMT and metastasis.183 EMT represents a pivotal biological process, playing a critical role beyond its well-established functions in embryogenesis and wound healing, particularly in the context of oncogenesis and tumour progression.184-186 This process entails a comprehensive reprogramming of epithelial cells, leading to a loss of their characteristic cellular adhesion and polarity, while simultaneously acquiring mesenchymal traits, including enhanced migratory and invasive capabilities.187-189 This transformation is instrumental in the malignant progression of neoplasms, contributing significantly to the increased metastatic potential and therapy resistance in cancer cells.190-192 At the core of EMT are intricate molecular mechanisms that orchestrate this cellular metamorphosis.193-195 Central to this process are a series of TFs, notably Snail, Twist and ZEB. These factors are responsible for initiating a cascade of genetic and epigenetic modifications that suppress epithelial markers and activate genes associated with the mesenchymal phenotype.121, 196-201 This transition is further accentuated by the reorganisation of the cytoskeleton and alterations in cell–cell and cell–matrix interactions. Additionally, post-translational modifications and non-coding RNA elements play a substantial role in fine tuning this process. The pathways that govern EMT mirror those involved in embryonic development, particularly TGF-β, Wnt, Hedgehog and Hippo signalling pathways, thus reflecting an intrinsic link between physiological developmental processes and pathological cancer progression.202, 203 Emerging research also highlights the role of redox signalling as a crucial modulator in the EMT process.204 The initiation of EMT is a response to a variety of stimuli within the TME.205 This includes, but is not limited to, growth factors, cytokines, hypoxic conditions and physical interactions with the surrounding ECM. Key signalling pathways such as those mediated by TGF-β, BMP, Wnt-β-catenin, Notch, Hedgehog and receptor tyrosine kinases are activated in response to these stimuli.206 These pathways converge to effectuate a shift in the cellular transcription program, which results in diminished cell–cell adhesion, changes in cytoskeletal dynamics and acquisition of mesenchymal characteristics. The intricate interplay and crosstalk among these pathways in response to environmental cues are essential in regulating EMT in both physiological and pathological contexts, including cancer development and progression. In the realm of cancer biology, the aberrant activation of EMT is linked to several malignancy-enhancing properties of tumour cells. These properties encompass increased cellular migration and invasiveness, augmented tumour stemness, and a notable enhancement in resistance to conventional chemotherapeutic and immunotherapeutic regimens. This underscores the critical role of EMT in the facilitation of tumour progression, metastasis and the often-observed therapeutic resistance in clinical oncology.207, 208 Given this, the exploration and targeting of EMT mechanisms offer a significant and promising avenue for therapeutic intervention. Such approaches aim to mitigate tumour metastasis and recurrence, presenting a potential paradigm shift in cancer treatment strategies. The understanding of EMT in cancer biology thus not only illuminates the intricate molecular and cellular dynamics underpinning tumour progression but also paves the way for novel and more effective therapeutic approaches. This knowledge is pivotal in developing targeted therapies that can potentially overcome the limitations of current treatment modalities and offer new hope in the fight against cancer.
11 EMT IN INVASIVE CANCER CELL DEVELOPMENT
In cancer metastasis, two of the micro-events are innovation (where cancer cells cross the epithelial cell barrier into the blood circulatory system) and extravasation (where cells migrate from the circulation into the entry-distant organ tissue). All of these events are regulated via a complex receptor-based interaction with multiple cellular signals.209 Metastatic cascades occur through the involvement of cancer cells, immune cells, matrix and blood vessels.210 Scientific evidence suggests that details and scrutiny have revealed that macrophages (Notch signalling provides the bridge between tumour cells and macrophages211), tumour cells and endothelial cells co-evolve in the tumour metastatic ecosystem in the TME. VEGF-A plays an exciting role (helping tumour cells to invade blood vessels) in metastasis.212 VEGF-A missed cells associated with immune surveillance (NK cells and T cells) and promoted tumour angiogenesis.213, 214 TME-based tumour cells facilitated EMT. The innervation of tumour cells and the increase in the population of circulating tumour cells (CTCs) are regulated via endosialin (CD128).215 EMT promotes the migration of cancer cells via blood circulation and secondary tumour formation. There is the secret involvement of Twist1, platelet-derived growth factor receptor expression and Src activation.216, 217 Recent advancements in scientific research indicate that cellular intravasation is not linked to EMT, this revelation adds a layer of complexity to our understanding of EMT.218
12 EMT IN CIRCULATING TUMOUR CELLS
CTCs behave like a seed for distant organ metastasis tumour formation.219 After reaching a distance, the accumulation of cancer cells in organs is still scientifically studied.220, 221 CTCs are also associated with a cancer diagnosis and multiple therapy outcomes.222, 223 CTCs carry EMT properties. The latest CTC capture technologies successfully detected epithelial and mesenchymal CTCs.224, 225 The diversity of CTC marker expression indicates multiple phases of epithelial and mesenchymal cells226, 227 and CTCs also express EMT-associated TFs.201 Some clinical evidence indicates that chemoresistance development in breast and pancreatic cancer is guided by EMT-associated CTCs.228, 229 Clinical gene profiling data indicate that TGF signalling signals higher expression presence in CTCs. Furthermore, EMT-related CTCs involve metastasis through E-cadherin downregulation and high vimentin expression.231 Finally, in EMT, CTCs are associated with changes in cellular adhesion phenomena, therapeutic resistance and metastasis regulation.232
13 MET IS THE OPPOSITE OF EMT
In metastatic cancer, when CTCs reach the distant organ, they reprogram function, transform into mesenchymal cells and initiate secondary tumour formation.184 Scientific evidence shows that tumour cells express both cells together, epithelial and mesenchymal.233 Mesenchymal cells of the secondary tumour site associated expression enrichment when marching with the primary site of mesenchymal tumour cells, indicating mesenchymal CTCs associated with secondary tumour formation.234 E-cadherin expression at the secondary site of the tumour is a sign of MET.235 MET has involvement in some major cancers (breast, ovarian and pancreatic). When examining breast cancer, tumour cells at the site of metastasis express more E-cadherin expression than the primary site.236 Some of the studies suggest that inflammation-associated breast cancer (ductal or lobular cancer) expresses E-cadherin equally at the primary and secondary tumour sites.237-239 Other scientific evidence mentions that MET leads to lung metastases240 and bone metastases in breast cancer.241, 215 E-cadherin presence in ovarian cancer and normal tissues is normal,242, 216 but metastatic ovarian cells express high E-cadherin content.243, 217 Pancreatic carcinoma-associated metastases are influenced by MET.244 One study reported that E-cadherin is high in pancreatic cancer. We have less information on MET compared to EMT.245, 246 EMT-related TFs play a crucial role in MET.122, 247, 248
14 INTERRELATION WITH EMT AND CANCER STEMNESS, DORMANCY AND SENESCENCE
In cancer, stem cell development is regulated via the EMT process.22 Various research suggests that the tumour cell creates a complex interlink between EMT, metastasis and stemness. The EMT initiation promotes the development of stem cells such as a micro-population in tumours.20, 249 This cell population enhances tumour formation and is also related to cancer metastasis.180, 250 EMT-TF Zeb1 regulates stemness by suppressing miRNA-200.251 CSCs display epithelial and mesenchymal phenotypes simultaneously, allowing them to undergo EMT. CSCs contribute to tumour development, metastasis and treatment resistance. Research evidence suggests that the influence of TGF-β, Snail1/Twist1 signalling pathways, induces breast epithelial to develop the metastasis nature and participate in EMT in the in vitro system.249 Notch signalling involves in pancreatic cancer EMT.252 Breast cancer-associated metastasis is led by stem cell-like cells.179 Different investigations refer that after an EMT event, several cancer cells develop stem cells naturally.253, 254 The JAK2/STAT3 signalling associated oral squamous cell carcinoma regarding MET and metastasis presence of CCL21/CCR7.255 We can predict breast cancer-related EMT and stemness-associated genomic expression, but based on this, cancer detection is the main challenge.256 In pancreatic cancer, CD133 is a marker for CSCs.257 Finally, several researchers suggest that EMT develops CSCs properties, leading cancer cells to migrate to distant organs and form secondary tumours.258 Cancer quiescence is associated with both phage EMT/MET and its influence through CSC quiescence.259 Snails are associated with slowing down cancer cell proliferation.260 The initiation and termination of the quiescent phase are not identified, and a cellular phenotypic change associated with the quiescent phase is not apparent in in vivo systems.244, 261 Initiation of EMT from quiescent breast cancer cells (MCF-7) expresses LOXL2 that develops CSCs property and leads to metastasis.262 Several pieces of scientific evidence indicate that senescence and EMT result in a complex association. Epithelial cells express ErbB2 to promote cancer cell senescence, and expression twist and ErbB2 play a role in initiating EMT and bypassing senescence.263 Activation of TGF, p53 cells is arrested in the senescence phase and this event inhibits EMT, so EMT may not be linked to senescence.264 Studies have shown that in vitro system cells are less expressed in E-cadherin and β-catenin.265 Some of the chemokines (IL-6, IL-8) promote senescent cells, EMT and metastasis (e.g., breast cancer cells).265, 266 The senescent fibroblast is involved in EMT and metastasis.267
15 EMT LEADS TO CANCER DRUG RESISTANCE
EMT-mediated drug resistance is regulated by tumour heterogeneity. Pharmacogenomics has shown an association between EMT and chemotherapy resistance.268 Breast cancer,269 bladder cancer270 and pancreatic cancer271 lead to drug resistance as a reason for tumour heterogeneity. To uncover the relationship between EMT and metastasis, researchers are experimenting on genetically modified mice.229, 230 TGF-β signalling is associated with drug resistance.272 Colorectal cancer EMT and drug resistance are associated with TGF-β signalling.230 Wnt, Hedgehog signalling pathways are associated with drug resistance.273, 274 EMT-related TFs regulate drug resistance.275 EMT-TFs are central to the phenomenon of drug resistance in cancer, representing a formidable challenge in the realm of oncology.121, 276, 277 EMT is a complex biological program where epithelial cancer cells lose their characteristic properties, such as cell polarity and adhesion, and acquire mesenchymal traits that include enhanced migratory capacity, invasiveness, and elevated resistance to apoptosis278-281. This transformation is regulated by a cadre of TFs, notably SNAIL (SNAIL1 and SNAIL2/SLUG), TWIST (TWIST1 and TWIST2), ZEB (ZEB1 and ZEB2) and others such as GATA3, SOX4 and PRRX1.173 These factors modulate the expression of a myriad of genes involved in cell adhesion (e.g., E-cadherin downregulation), cytoskeletal reorganisation and ECM remodelling. The implications of EMT-TFs in cancer drug resistance are profound and multifactorial:
Phenotypic plasticity and drug resistance: EMT-TFs bestow upon cancer cells a remarkable level of plasticity, enabling them to adapt and survive in the face of pharmacological stress. This adaptability often results in the development of resistance to a variety of chemotherapeutic agents. For instance, SNAIL and TWIST have been implicated in promoting resistance to platinum-based compounds, anthracyclines and taxanes, commonly by activating survival pathways and inhibiting pro-apoptotic mechanisms.178
Cancer stem cells and therapy resistance: EMT-TFs contribute significantly to the maintenance and enrichment of CSCs, a subset of tumour cells characterised by self-renewal capacity and high resistance to conventional and targeted therapies. CSCs are less responsive to treatments due to their quiescent nature, enhanced DNA repair mechanisms, and the expression of multiple drug resistance genes, including ABC transporters. EMT-TFs, particularly ZEB1 and SLUG, are known to induce stemness features in cancer cells, thus facilitating the survival and propagation of these resistant cells.179
Interactions with signalling pathways: EMT-TFs interface with numerous critical cellular signalling cascades, such as TGF-β, Wnt, Notch, and PI3K/AKT. These interactions lead to altered cellular processes, including augmented survival signalling, evasion of programmed cell death, metabolic reprogramming and immune evasion, all contributing to heightened drug resistance.180
Regulatory networks and environmental influences: The expression and activity of EMT-TFs are governed by a complex interplay of upstream regulatory mechanisms, including growth factors (e.g., EGF, HGF), cytokines and stress signals. Additionally, the TME, characterised by conditions such as hypoxia, inflammation and immune infiltration, can modulate EMT-TF expression and function. Hypoxic conditions, for instance, can induce EMT and associated drug resistance through HIF-1α-mediated upregulation of EMT-TFs.181
Clinical implications and therapeutic targeting: Understanding the role of EMT-TFs in drug resistance has profound clinical implications. It suggests the need for a holistic approach to cancer therapy, which includes targeting EMT pathways, modulating the TME and employing strategies to eradicate CSCs. Furthermore, biomarkers based on EMT-TF expression and activity could be pivotal in predicting drug response and tailoring personalised treatment regimens.282, 268
EMT-TFs such as SNAIL, TWIST, ZEB and others represent key molecular orchestrators in the development of drug resistance in cancer.283-285 Their role extends beyond the induction of EMT; they are central to the regulation of CSC properties, interaction with critical signalling pathways, and response to environmental stimuli. Comprehensive understanding and strategic targeting of these factors are essential for overcoming EMT-TF-mediated drug resistance and improving therapeutic outcomes in cancer, as summarised in Table 1.
TABLE 1.
Comprehensive overview of epithelial–mesenchymal transition (EMT) transcription factors and their multifaceted roles in cancer drug resistance: key mechanisms, signalling pathway interactions and clinical implications.
EMT transcription factor
Role in EMT
Contribution to drug resistance
Interaction with signalling pathways
Clinical implications
SNAIL (SNAIL1 and SNAIL2/SLUG)
Regulates genes controlling cell adhesion and cytoskeletal dynamics.
Promotes resistance to chemotherapeutic drugs through survival pathway activation and apoptosis inhibition.
Interacts with TGF-β, Wnt and Notch signalling pathways.
Potential biomarker for predicting drug response; target for therapeutic intervention.
TWIST (TWIST1 and TWIST2)
Involved in the initiation of the EMT process, regulating genes related to cell morphology.
Associated with resistance to platinum-based compounds, anthracyclines and taxanes.
Modulates PI3K/AKT and TGF-β pathways, affecting cell survival and proliferation.
Important in personalised treatment strategies; target for overcoming drug resistance.
ZEB (ZEB1 and ZEB2)
Controls gene expression for cell adhesion and extracellular matrix remodelling.
Enhances cancer stem cell-like properties, leading to inherent treatment resistance.
Influences Wnt and Notch pathways, critical in stemness and drug resistance.
Key in CSC-targeted therapies and in developing anti-resistance strategies.
GATA3
Influences cell differentiation and development, plays a role in EMT induction.
Implicated in resistance mechanisms, particularly in breast cancer.
Associated with TGF-β signalling in some cancer types.
Can be a prognostic marker and therapeutic target in specific cancer types.
SOX4
Regulates genes for cell migration and invasion.
Contributes to therapeutic resistance via modulation of cell survival and invasion.
Interacts with various growth factor signalling pathways.
Target for novel therapeutics aimed at reducing metastasis and resistance.
PRRX1
Contributes to mesenchymal differentiation and cell migration.
Plays a role in the resistance to targeted therapies.
Participates in signalling pathways involved in cell migration and invasion.
Implications for targeted therapy development, especially in metastatic cancers.
From a cancer clinical perspective, EMT markers are divided into two distinct groups, one group is a protein marker and the other group is an RNA marker. The whole EMT process is divided into three groups, EMT type I (involved in organogenesis), EMT type II (wound healing and fibroblast development) and EMT type III (involved in cell migration and metastasis).286 EMT-related markers, detection approaches and their limitations simplify the pathway and are outlined in Table 2.
EMT is defined by the loss of cell-to-cell adhesions, apicobasal polarity and the development of more invasiveness.298 EMT has become an increasingly intriguing target for the development of innovative treatment approaches as it is involved in a variety of activities related to malignant transformation. Anti-EMT treatment approaches have the potential to reduce the phenomenon of cancer metastasis, inhibit the development of CSCs and inhibit the development of therapeutic resistance.299 There are four main targeting approaches (Figure 4) that have recently been proposed to combat EMT298: (1) inhibit EMT-promoting signalling in the TME, (2) target signalling pathways that are related to EMT, (3) target mesenchymal cells markers expression (which are related with mesenchymal cells nature development), and (4) inhibition of MET process.
Epithelial–mesenchymal transition (EMT) targeting approaches (Ref. 298). Created with BioRender.com. DSP, NanoString's Digital Spatial Profiling; RNA-ISH, RNA in situ hybridization; RT-PCR, Reverse Transcription Polymerase Chain Reaction.
EMT is also a process involved in some basic cellular processes (tissue repair, organ development). Cancer required more clarity about the upstream signalling cascade. Notch, Wnt and TGF-β signalling pathways are involved in embryonic development and EMT in cancer.299-301 Because EMT-TFs are implicated in carcinogenesis, there is increasing interest in blocking EMT as a therapeutic approach. The majority of anti-EMT drugs on the market now focus on preventing upstream EMT inducers. Scientific research requires a dedicated detailed exploration of the EMT research area and the development of an efficient therapeutic approach to cancer.302 Several EMT targeting approaches are listed in Table 3.
TABLE 3.
Therapeutic approaches for epithelial–mesenchymal transition (EMT).
Abbreviations: CN, completed (no results available); CS, completed successfully; CU, completed unsuccessfully; NF-κB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; O, ongoing; P, planned; T, terminated.
18 CHALLENGES OF EMT RESEARCH
Cancer researchers suggest that future researchers need to be more concerned about EMT-TFs and other EMT-related factors. This thing helps more prices look meaner at the EMT with more detail. The tumourigenic role of EMT-TFs has less chance of diversity with organs and tissues. The mutation associated with the TME affects the interrelationship of EMT-TFs and stem cells in cancer. The introduction of the in vivo system and the knock-out approach requires an experimental analysis. EMT-TFs have a significant role in epigenetic reprogramming.123 Cell signalling mediated by EMT-TFs and miRNAs is one of the exciting fields of future EMT research. Cell culture-mediated research examines the relationships between MET and cancer metastases at the primary level.27, 316-318 Several studies report that cancer metastases are not dependent on EMT.229, 230 CRISPR-Cas9, tumour organoids and dual recombinase systems introduce a new dimension to EMT research. The practical, pervasive therapeutic development is required for EMT drug targeting research. The major challenges in EMT research are (a) TME related to multiple factors affecting EMT, (b) EMT-TFs related to complex EMT development, (c) EMT-related gene expression occurs in a specific tissue, (d) significantly less information about EMT-TFs and the interrelationship between cell signals, (e) we do not know whether epithelial to mesenchymal cell transformation is mediated by the same cell or whether the cells also contribute to participation, (f) the same phenotypic cancer cells throughout develops malignancy of cancer or other subpopulation, (g) it is unclear why and how EMT and cancer cell strains develop, and (h) the most interesting event is the overgrowth of cancer cell population bearing mesenchymal cells derived from CSCs, which is not yet is clear.4 In the future, we need the most innovative research framework Diginin in combination with stem cell biology, biophysics, mathematical models and systems biology that has led to effective therapeutic development. Advanced EMT research needs to focus on the single-cell level (this process needs to be combined with imaging, tracking, gene expression and epigenetic analysis). This multidisciplinary associated investigation assists us in understanding the diversity of EMT.140
19 FUTURE DIRECTIONS IN EMT-RELATED DIAGNOSTICS OR THERAPEUTICS
The future of diagnostics and therapeutics in relation to EMT is poised to make significant advancements, particularly in the realm of oncology.319 As our understanding of EMT deepens, its potential as a target for cancer diagnostics and therapeutics becomes increasingly apparent.299, 320 In diagnostics, the focus is shifting towards the development of biomarkers that can identify EMT states within tumours.286 This involves detecting specific molecular signatures associated with EMT, such as the expression levels of key TFs such as Snail, Twist and ZEB, or changes in the expression of epithelial and mesenchymal markers.321, 322 The use of advanced imaging techniques and liquid biopsies to detect these markers in real-time could provide critical insights into tumour progression and metastatic potential, enabling personalised treatment strategies. In therapeutics, the emphasis is on targeting the molecular pathways that drive EMT.323 This could involve the development of drugs that inhibit key signalling molecules or pathways implicated in EMT, such as TGF-β, Wnt and Hedgehog.324 Another promising approach is the use of epigenetic therapies that can reverse the epigenetic modifications driving the EMT process.325, 326 Additionally, there is growing interest in exploiting the unique metabolic characteristics of cells undergoing EMT, as these cells often exhibit altered metabolic profiles that could be targeted for therapy.327 Moreover, the role of the TME in EMT presents another therapeutic avenue. Therapies aimed at modifying the TME, such as targeting the ECM or modulating immune cell interactions, could disrupt the signals that trigger EMT.328 Immunotherapy, particularly therapies that enhance the immune system's ability to recognise and attack cancer cells undergoing EMT, is another area of active research.175, 224 Finally, the potential of combination therapies that target multiple aspects of EMT simultaneously is being explored.329 This could involve combining traditional chemotherapeutics with EMT-targeted drugs, or using immunotherapy in conjunction with agents that reverse EMT.330 The goal of such combination therapies would be to tackle the tumour from multiple angles, increasing the likelihood of treatment success. The future directions in EMT-related diagnostics and therapeutics are geared towards a more nuanced understanding of tumour biology and the development of more targeted, effective treatment strategies.207 This evolution in cancer treatment promises to enhance patient outcomes, reduce side effects and provide new hope in the battle against cancer.
20 CONCLUSION
EMT emerges as a critical determinant in the efficient spread of metastases, a fact robustly supported by a wealth of research involving cancer cell lines, mouse tumour models and analyses of human tumour tissues. The significance of a partial and reversible EMT, which allows disseminated tumour cells to revert to an epithelial phenotype for metastatic colonisation at distant sites, remains an area shrouded in uncertainty. Equally ambiguous is the origin of mesenchymal cells implicated in tissue repair and pathological conditions such as tissue fibrosis, tumour invasiveness and metastasis. Recent evidence, however, increasingly identifies EMT as a key contributor to the generation of these cells. Numerous studies and clinical trials have reinforced the notion that EMT is an indispensable mechanism in the propagation of metastatic disease. This article has highlighted that while the primary drivers of EMT are becoming increasingly understood, there remains a pressing need for further research to fully elucidate the complexities of this intricate biological process. Notably, the development of novel pharmacological interventions targeting EMT-related signalling pathways stands at the forefront of contemporary research efforts. These strategies aim to maintain cancer cells in an epithelial state, which is less conducive to tumour progression and metastasis. The insights gained from studying EMT not only offer potential new markers for assessing disease severity but also herald a significant shift in therapeutic approaches to cancer treatment. By focusing on the intricate network of pathways and factors involved in EMT, we are on the cusp of unlocking novel, more effective modalities of intervention. This paradigm shift in understanding and manipulating EMT processes is poised to make a substantial impact on the future of cancer therapy, marking a pivotal moment in the ongoing battle against this formidable disease.
AUTHOR CONTRIBUTIONS
Original draft writing: Nobendu Mukerjee, Sagnik Nag, Bikramjit Bhattacharya, Divya Mirgh, Dattatreya Mukherjee. Scientific Illustration Development: Nobendu Mukerjee. Review: Athanasios Alexiou, Manab Deb Adhikari, Krishnan Anand, Raman Muthusamy. Final Review and editing: Sukhamoy Gorai, Nanasaheb Thorat.
ACKNOWLEDGEMENTS
N.D.Thorat acknowledge funding under the Science Foundation Ireland and Irish Research Council (SFI-IRC) Pathway Programme (21/PATH-S/9634).
Open access funding provided by IReL.
CONFLICT OF INTEREST STATEMENT
The authors declare they have no conflicts of interest.
ETHICS STATEMENT
There are no human or animal studies in this paper.
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
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