Abstract:Based on the transcriptional regulatory mechanisms between microRNA-200 and transcription factor ZEB in an individual cancer cell, a minimal dynamic model is proposed to study the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) processes of cancer cells. It is shown that each cancer cell can exit in any of three phenotypic states: the epithelial (E) state, the mesenchymal (M) state, and the epithelial/mesenchymal (E/M) hybrid state, and the state of cancer cell can interconv… Show more
“…However, these switches are actually taking place under a dynamic model, where in numerous cases the cells only achieve a hybrid state-epithelial/mesenchymal (E/M), having mixed characteristics between the epithelial and mesenchymal phenotype. Under the hybrid form, the cells can migrate together as clusters and can be found in the bloodstream of patients under the term of clusters of circulating tumor cells (CTCs) [44,45]. Early in 2011, it was shown for the first time the presence of hybrid CTCs that co-express keratin and vimentin in the blood of metastatic NSCLC patients [46].…”
Section: Hypoxia and Metastasis: The Implication Of The Hypoxic Effecmentioning
Hypoxia represents a frequent player in a number of malignancies, contributing to the development of the neoplastic disease. This review will discuss the means by which hypoxia powers the mechanisms behind cancer progression, with a majority of examples from lung cancer, the leading malignancy in terms of incidence and mortality rates (the frequent reference toward lung cancer is also for simplification purposes and follow up of the global mechanism in the context of a disease). The effects induced by low oxygen levels are orchestrated by hypoxia-inducible factors (HIFs) which regulate the expression of numerous genes involved in cancer progression. Hypoxia induces epithelial-to-mesenchymal transition (EMT) and metastasis through a complex machinery, by mediating various pathways such as TGF-β, PI3k/Akt, Wnt, and Jagged/Notch. Concomitantly, hypoxic environment has a vast implication in angiogenesis by stimulating vessel growth through the HIF-1α/VEGF axis. Low levels of oxygen can also promote the process through several other secondary factors, including ANGPT2, FGF, and HGF. Metabolic adaptations caused by hypoxia include the Warburg effect—a metabolic switch to glycolysis—and GLUT1 overexpression. The switch is achieved by directly increasing the expression of numerous glycolytic enzymes that are isoforms of those found in non-malignant cells.
“…However, these switches are actually taking place under a dynamic model, where in numerous cases the cells only achieve a hybrid state-epithelial/mesenchymal (E/M), having mixed characteristics between the epithelial and mesenchymal phenotype. Under the hybrid form, the cells can migrate together as clusters and can be found in the bloodstream of patients under the term of clusters of circulating tumor cells (CTCs) [44,45]. Early in 2011, it was shown for the first time the presence of hybrid CTCs that co-express keratin and vimentin in the blood of metastatic NSCLC patients [46].…”
Section: Hypoxia and Metastasis: The Implication Of The Hypoxic Effecmentioning
Hypoxia represents a frequent player in a number of malignancies, contributing to the development of the neoplastic disease. This review will discuss the means by which hypoxia powers the mechanisms behind cancer progression, with a majority of examples from lung cancer, the leading malignancy in terms of incidence and mortality rates (the frequent reference toward lung cancer is also for simplification purposes and follow up of the global mechanism in the context of a disease). The effects induced by low oxygen levels are orchestrated by hypoxia-inducible factors (HIFs) which regulate the expression of numerous genes involved in cancer progression. Hypoxia induces epithelial-to-mesenchymal transition (EMT) and metastasis through a complex machinery, by mediating various pathways such as TGF-β, PI3k/Akt, Wnt, and Jagged/Notch. Concomitantly, hypoxic environment has a vast implication in angiogenesis by stimulating vessel growth through the HIF-1α/VEGF axis. Low levels of oxygen can also promote the process through several other secondary factors, including ANGPT2, FGF, and HGF. Metabolic adaptations caused by hypoxia include the Warburg effect—a metabolic switch to glycolysis—and GLUT1 overexpression. The switch is achieved by directly increasing the expression of numerous glycolytic enzymes that are isoforms of those found in non-malignant cells.
“…3 ), thereby priming the cells for a complete EMT transition and effective peritoneal invasion. Kinetic models of EMT that incorporate multiple states of EMT [ 182 ] will be required to address this in detail in the future. Fig.…”
Section: Tgfβ and Emt In The Metastatic Epithelial Ovarian Cancer Envmentioning
Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell–cell junctions, cell–matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-β (TGFβ) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFβ can act as either a tumor suppressor or promoter in cancer, TGFβ exhibits its pro-tumorigenic functions at least in part via EMT. TGFβ regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFβ based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFβ isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.
“…In the presence of TGF–β, Notch1 has been observed to inhibit Notch3 and activate ZEB1, which in turn has been associated with the promotion of hybrid EMT [ 61 ]. Numerical simulations have provided insight that the noise and the time of delay act oppositely on the expression of ZEB, which in turn determines the transition of the E/M spectrum [ 62 ]. Bioinformatic strategy observed that the nuclear factor of activated T-cells and specificity protein 1 concerted as master regulators for facilitating a hybrid E/M phenotype in non-transformed mammary gland cells and colorectal cancer cells [ 6 ].…”
Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon.
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