scholarly journals Phase transitions of biological phenotypes by means of a prototypical PDE model

2020 ◽  
Vol 11 (1) ◽  
pp. 1-17
Author(s):  
C. Mascia ◽  
P. Moschetta ◽  
C. Simeoni
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Essential Feature ◽  
Tumor Development ◽  
Mesenchymal Transition ◽  
Pde Model ◽  
Mesenchymal To Epithelial Transition ◽  
Parabolic Pde ◽  
Epithelial Phenotype ◽  
Explicit Finite Difference ◽  
Speed Of Propagation

AbstractThe basic investigation is the existence and the (numerical) observability of propagating fronts in the framework of the so-called Epithelial-to-Mesenchymal Transition and its reverse Mesenchymal-to-Epithelial Transition, which are known to play a crucial role in tumor development. To this aim, we propose a simplified one-dimensional hyperbolic-parabolic PDE model composed of two equations, one for the representative of the epithelial phenotype, and the second describing the mesenchymal phenotype. The system involves two positive constants, the relaxation time and a measure of invasiveness, moreover an essential feature is the presence of a nonlinear reaction function, typically assumed to be S-shaped. An identity characterizing the speed of propagation of the fronts is proven, together with numerical evidence of the existence of traveling waves. The latter is obtained by discretizing the system by means of an implicit-explicit finite difference scheme, then the algorithm is validated by checking the capability of the so-called LeVeque–Yee formula to reproduce the value of the speed furnished by the above cited identity. Once such justification has been achieved, we concentrate on numerical experiments relative to Riemann initial data connecting two stable stationary states of the underlying ODE model. In particular, we detect an explicit transition threshold separating regression regimes from invasive ones, which depends on critical values of the invasiveness parameter. Finally, we perform an extensive sensitivity analysis with respect to the system parameters, exhibiting a subtle dependence for those close to the threshold values, and we postulate some conjectures on the propagating fronts.

scholarly journals Isoliquiritigenin Inhibits Ovarian Cancer Metastasis by Reversing Epithelial-to-Mesenchymal Transition

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3725 ◽  
Author(s):  
Chen Chen ◽  
Shuang Huang ◽  
Chang-Liang Chen ◽  
Sing-Bing Su ◽  
Dong-Dong Fang
Keyword(s):  
Ovarian Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Development ◽  
Skov3 Cell ◽  
Anticancer Activities ◽  
Mesenchymal Transition ◽  
Epithelial Phenotype ◽  
Ovary Tumor

The epithelial-to-mesenchymal transition (EMT) plays a prominent role in cancer metastasis. Isoliquiritigenin (ISL), one of the flavonoids in licorice, has been shown to exhibit anticancer activities in many cancer types through various mechanisms. However, it is unknown whether ISL impacts the EMT process. Here, we show that ISL is able to suppress mesenchymal features of ovarian cancer SKOV3 and OVCAR5 cells, evidenced by an apparent morphological change from a mesenchymal to an epithelial phenotype and reduced levels of mesenchymal markers accompanied by the gain of E-cadherin expression. The suppression of EMT is also supported by the observed decrease in cell migration and in vitro invasion upon ISL treatment. Moreover, we show that ISL effectively blocks the intraperitoneal xenograft development of the SKOV3 cell line and prolonged the survival of tumor-bearing mice. These data suggest that ISL inhibits intraperitoneal ovary tumor development through the suppression of EMT, indicating that ISL may be an effective therapeutic agent against ovarian cancer.

scholarly journals Deciphering the Importance of Glycosphingolipids on Cellular and Molecular Mechanisms Associated with Epithelial-to-Mesenchymal Transition in Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 62
Author(s):  
Cécile Cumin ◽  
Yen-Lin Huang ◽  
Arun Everest-Dass ◽  
Francis Jacob
Keyword(s):  
Cell Surface ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Membrane Integrity ◽  
Tumor Development ◽  
Membrane Lipid ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Plasma Membrane Lipid ◽  
Metastatic Sites

Every living cell is covered with a dense and complex layer of glycans on the cell surface, which have important functions in the interaction between cells and their environment. Glycosphingolipids (GSLs) are glycans linked to lipid molecules that together with sphingolipids, sterols, and proteins form plasma membrane lipid rafts that contribute to membrane integrity and provide specific recognition sites. GSLs are subdivided into three major series (globo-, ganglio-, and neolacto-series) and are synthesized in a non-template driven process by enzymes localized in the ER and Golgi apparatus. Altered glycosylation of lipids are known to be involved in tumor development and metastasis. Metastasis is frequently linked with reversible epithelial-to-mesenchymal transition (EMT), a process involved in tumor progression, and the formation of new distant metastatic sites (mesenchymal-to-epithelial transition or MET). On a single cell basis, cancer cells lose their epithelial features to gain mesenchymal characteristics via mechanisms influenced by the composition of the GSLs on the cell surface. Here, we summarize the literature on GSLs in the context of reversible and cancer-associated EMT and discuss how the modification of GSLs at the cell surface may promote this process.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

scholarly journals miRNA proxy approach reveals hidden functions of glycosylation

2015 ◽  
Vol 112 (23) ◽  
pp. 7327-7332 ◽  
Author(s):  
Tomasz Kurcon ◽  
Zhongyin Liu ◽  
Anika V. Paradkar ◽  
Christopher A. Vaiana ◽  
Sujeethraj Koppolu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Epithelial To Mesenchymal Transition ◽  
Biological Function ◽  
Regulatory Elements ◽  
Rapid Identification ◽  
Mesenchymal Transition ◽  
Disease States ◽  
Mesenchymal To Epithelial Transition ◽  
Genes Encoding ◽  
Target Network

Glycosylation, the most abundant posttranslational modification, holds an unprecedented capacity for altering biological function. Our ability to harness glycosylation as a means to control biological systems is hampered by our inability to pinpoint the specific glycans and corresponding biosynthetic enzymes underlying a biological process. Herein we identify glycosylation enzymes acting as regulatory elements within a pathway using microRNA (miRNA) as a proxy. Leveraging the target network of the miRNA-200 family (miR-200f), regulators of epithelial-to-mesenchymal transition (EMT), we pinpoint genes encoding multiple promesenchymal glycosylation enzymes (glycogenes). We focus on three enzymes, beta-1,3-glucosyltransferase (B3GLCT), beta-galactoside alpha-2,3-sialyltransferase 5 (ST3GAL5), and (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (ST6GALNAC5), encoding glycans that are difficult to analyze by traditional methods. Silencing these glycogenes phenocopied the effect of miR-200f, inducing mesenchymal-to-epithelial transition. In addition, all three are up-regulated in TGF-β–induced EMT, suggesting tight integration within the EMT-signaling network. Our work indicates that miRNA can act as a relatively simple proxy to decrypt which glycogenes, including those encoding difficult-to-analyze structures (e.g., proteoglycans, glycolipids), are functionally important in a biological pathway, setting the stage for the rapid identification of glycosylation enzymes driving disease states.

scholarly journals CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Alessandra Righetti ◽  
Matteo Giulietti ◽  
Berina Šabanović ◽  
Giulia Occhipinti ◽  
Giovanni Principato ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Invasion ◽  
Epithelial To Mesenchymal Transition ◽  
Current Knowledge ◽  
Tumor Development ◽  
Physiological Role ◽  
Mesenchymal Transition ◽  
Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

scholarly journals Lamins in Lung Cancer: Biomarkers and Key Factors for Disease Progression through miR-9 Regulation?

Cells ◽  
2018 ◽  
Vol 7 (7) ◽  
pp. 78 ◽  
Author(s):  
Julien Guinde ◽  
Diane Frankel ◽  
Sophie Perrin ◽  
Valérie Delecourt ◽  
Nicolas Lévy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Development ◽  
Nuclear Lamina ◽  
Metastatic Potential ◽  
Disease Diagnosis ◽  
Carcinoma Cells ◽  
Scaffolding Protein ◽  
Mesenchymal Transition ◽  
Cancer Subtypes

Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or metastatic cancers. In this context, the identification of new biomarkers is essential to improve the differential diagnosis between cancer subtypes, to select the most appropriate therapy, and to establish prognostic correlations. Nuclear abnormalities are hallmarks of carcinoma cells and are used as cytological diagnostic criteria of malignancy. Lamins (divided into A- and B-types) are localized in the nuclear matrix comprising nuclear lamina, where they act as scaffolding protein, involved in many nuclear functions, with regulatory effects on the cell cycle and differentiation, senescence and apoptosis. Previous studies have suggested that lamins are involved in tumor development and progression with opposite results concerning their prognostic role. This review provides an overview of lamins expression in lung cancer and the relevance of these findings for disease diagnosis and prognosis. Furthermore, we discuss the link between A-type lamins expression in lung carcinoma cells and nuclear deformability, epithelial to mesenchymal transition, and metastatic potential, and which mechanisms could regulate A-type lamins expression in lung cancer, such as the microRNA miR-9.

scholarly journals Cathepsin B Is Upregulated and Mediates ECM Degradation in Colon Adenocarcinoma HT29 Cells Overexpressing Snail

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 203 ◽  
Author(s):  
Jakub Kryczka ◽  
Izabela Papiewska-Pajak ◽  
M. Anna Kowalska ◽  
Joanna Boncela
Keyword(s):  
Cathepsin B ◽  
Epithelial To Mesenchymal Transition ◽  
Early Stage ◽  
Tumor Development ◽  
Colon Adenocarcinoma ◽  
Mesenchymal Cell ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Colon And Rectum ◽  
Phenotypic Shift

During tumor development and ongoing metastasis the acquisition of mesenchymal cell traits by epithelial carcinoma cells is achieved through a programmed phenotypic shift called the epithelial-to-mesenchymal transition, EMT. EMT contributes to increased cancer cell motility and invasiveness mainly through invadosomes, the adhesion structures that accompany the mesenchymal migration. The invadosomes and their associated proteases restrict protease activity to areas of the cell in direct contact with the ECM, thus precisely controlling cell invasion. Our data prove that Snail-overexpressing HT-29 cells that imitate the phenotype of colon cancer cells in the early stage of the EMT showed an increase in the expression and pericellular activity of cathepsin B. It appears that the pericellular localization of cathepsin B, also observed in colon and rectum adenocarcinoma tissue samples, plays a key role in its function.

scholarly journals The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 858 ◽  
Author(s):  
Burcu Sengez ◽  
Ilkin Aygün ◽  
Huma Shehwana ◽  
Neslihan Toyran ◽  
Sanem Tercan Avci ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Biological Processes ◽  
Comprehensive Understanding ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Strong Candidate ◽  
Acute Changes ◽  
Epithelial State ◽  
E Cadherin

The epithelial to mesenchymal transition (EMT) and the mesenchymal to epithelial transition (MET) are two critical biological processes that are involved in both physiological events such as embryogenesis and development and also pathological events such as tumorigenesis. They present with dramatic changes in cellular morphology and gene expression exhibiting acute changes in E-cadherin expression. Despite the comprehensive understanding of EMT, the regulation of MET is far from being understood. To find novel regulators of MET, we hypothesized that such factors would correlate with Cdh1 expression. Bioinformatics examination of several expression profiles suggested Elf3 as a strong candidate. Depletion of Elf3 at the onset of MET severely impaired the progression to the epithelial state. This MET defect was explained, in part, by the absence of E-cadherin at the plasma membrane. Moreover, during MET, ELF3 interacts with the Grhl3 promoter and activates its expression. Our findings present novel insights into the regulation of MET and reveal ELF3 as an indispensable guardian of the epithelial state. A better understanding of MET will, eventually, lead to better management of metastatic cancers.

scholarly journals Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype

2016 ◽  
Vol 13 (118) ◽  
pp. 20151106 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Aaron Goldman ◽  
Mika Pietilä ◽  
Sendurai A. Mani ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Cell Communication ◽  
Notch Signalling ◽  
Circulating Tumour Cells ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Key Players

Metastasis can involve repeated cycles of epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that allows the migration of adhering cells to form a cluster of circulating tumour cells. These clusters can be apoptosis-resistant and possess an increased metastatic propensity as compared to the cells that undergo a complete EMT (mesenchymal cells). Hence, identifying the key players that can regulate the formation and maintenance of such clusters may inform anti-metastasis strategies. Here, we devise a mechanism-based theoretical model that links cell–cell communication via Notch-Delta-Jagged signalling with the regulation of EMT. We demonstrate that while both Notch-Delta and Notch-Jagged signalling can induce EMT in a population of cells, only Jagged-dominated Notch signalling, but not Delta-dominated signalling, can lead to the formation of clusters containing hybrid E/M cells. Our results offer possible mechanistic insights into the role of Jagged in tumour progression, and offer a framework to investigate the effects of other microenvironmental signals during metastasis.

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