The Epithelial to Mesenchymal Transition and Metastatic Progression in Carcinoma

1996 ◽  
Vol 2 (1) ◽  
pp. 83-96 ◽  
Author(s):  
Christine Gilles ◽  
Erik W. Thompson
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Metastatic Progression ◽  
Mesenchymal Transition

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

2018 ◽  
Vol 39 (01) ◽  
pp. 053-069 ◽  
Author(s):  
Serena Mancarella ◽  
Antonio Cigliano ◽  
Annarita Chieti ◽  
Gianluigi Giannelli ◽  
Francesco Dituri
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Large Fraction ◽  
Poor Response ◽  
Tumor Promoter ◽  
Molecular Heterogeneity ◽  
Metastatic Progression ◽  
Functional Link ◽  
Mesenchymal Transition

AbstractTherapeutic attempts to treat hepatocellular carcinoma (HCC) frequently result in a poor response or treatment failure. The efficacy of approved drugs and survival expectancies is affected by an ample degree of variability that can be explained at least in part by the enormous between-patient cellular and molecular heterogeneity of this neoplasm. Transforming growth factor-β (TGF-β) is hyperactivated in a large fraction of HCCs, where it influences complex interactive networks covering multiple cell types and a plethora of other local soluble ligands, ultimately establishing several malignancy traits. This cytokine boosts the invasiveness of cancerous epithelial cells through promoting the epithelial-to-mesenchymal transition program, but also skews the phenotype of immune cells toward a tumor-supporting status. Here, we discuss recent strategies pursued to offset TGF-β-dependent processes that promote metastatic progression and immune surveillance escape in solid cancers, including HCC. Moreover, we report findings indicating that TGF-β reduces the expression of the proinflammatory factors CCL4 and interleukin-1β (IL-1β in human ex vivo treated HCC tissues. While this is consistent with the anti-inflammatory properties of TGF-β, whether it is an outright tumor promoter or suppressor is still a matter of some debate. Indeed, IL-1β has also been shown to support angiogenesis and cell invasiveness in some cancers. In addition, we describe an inhibitory effect of TGF-β on the secretion of CCL2 and CXCL1 by HCC-derived fibroblasts, which suggests the existence of an indirect stroma-mediated functional link between TGF-β and downstream immunity.

scholarly journals Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Antonietta Rosella Farina ◽  
Lucia Cappabianca ◽  
Michela Sebastiano ◽  
Veronica Zelli ◽  
Stefano Guadagni ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Tumour Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Protein Isoforms ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Cell Immortalization ◽  
Oncogene Activation ◽  
The Many

Abstract Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.

scholarly journals A comprehensive framework for analysis of microRNA sequencing data in metastatic colorectal cancer

NAR Cancer ◽  
2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Eirik Høye ◽  
Bastian Fromm ◽  
Paul H M Böttger ◽  
Diana Domanska ◽  
Annette Torgunrud ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Metastatic Progression ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Mesenchymal Transition ◽  
Starting Point ◽  
Microrna Sequencing ◽  
Metastatic Sites

ABSTRACT Although microRNAs (miRNAs) contribute to all hallmarks of cancer, miRNA dysregulation in metastasis remains poorly understood. The aim of this work was to reliably identify miRNAs associated with metastatic progression of colorectal cancer (CRC) using novel and previously published next-generation sequencing (NGS) datasets generated from 268 samples of primary (pCRC) and metastatic CRC (mCRC; liver, lung and peritoneal metastases) and tumor adjacent tissues. Differential expression analysis was performed using a meticulous bioinformatics pipeline, including only bona fide miRNAs, and utilizing miRNA-tailored quality control and processing. Five miRNAs were identified as up-regulated at multiple metastatic sites Mir-210_3p, Mir-191_5p, Mir-8-P1b_3p [mir-141–3p], Mir-1307_5p and Mir-155_5p. Several have previously been implicated in metastasis through involvement in epithelial-to-mesenchymal transition and hypoxia, while other identified miRNAs represent novel findings. The use of a publicly available pipeline facilitates reproducibility and allows new datasets to be added as they become available. The set of miRNAs identified here provides a reliable starting-point for further research into the role of miRNAs in metastatic progression.

scholarly journals A chemical screen based on an interruption of zebrafish gastrulation identifies the HTR2C inhibitor Pizotifen as a suppressor of EMT-mediated metastasis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Joji Nakayama ◽  
Lora Tan ◽  
Yan Li ◽  
Boon Cher Goh ◽  
Shu Wang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Serotonin Receptor ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Human Cancer ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Chemical Screen

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

scholarly journals Dynamic plasticity within the EMT spectrum, rather than static mesenchymal traits, drives tumor heterogeneity and metastatic progression of breast cancers

2021 ◽  
Author(s):  
Meredith S. Brown ◽  
Behnaz Abdollahi ◽  
Owen M. Wilkins ◽  
Priyanka Chakraborty ◽  
Nevena B. Ognjenovic ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Prognostic Significance ◽  
Cancer Cell Line ◽  
Breast Cancers ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
The Stability ◽  
Derivatives Of ◽  
Selection Of

AbstractThe Epithelial-to-Mesenchymal Transition (EMT) is a developmental cellular program frequently coopted by cancer cells1 and is a key contributor to both heterogeneity in solid tumors2–4 and later stage chemo-resistance and metastasis5,6. Rather than being a switch from an epithelial to a mesenchymal state, increasing evidence points to the existence of intermediate EMT states, wherein cells co-express both epithelial and mesenchymal traits7–13. Multiple stable intermediate EMT states possessing unique characteristics exist across the EMT spectrum7,8,14,15, contributing to the complex heterogeneity of tumors to promote metastasis16. While much work has been carried out identifying and characterizing EMT-inducing transcription factors17–20, the transcriptional and epigenetic networks responsible for the stability and maintenance of the midpoints along the EMT spectrum are poorly defined. In addition, there are currently no approaches to identifying and quantifying intermediate EMT subpopulations within patient tumors to evaluate their prognostic significance. Using clonally isolated derivatives of the SUM149PT breast cancer cell line, we systematically interrogate how each EMT state independently contributes to heterogeneity and influences metastatic progression, uncovering the role of RUNX2 in stabilizing certain intermediate states. Using SUM149PT-derived tumors as a training set, we develop an entropy-based model to quantify phenotypic heterogeneity and EMT status. Remarkably, the majority of cell states captured in the SUM149PT model are represented in a selection of patient tumors, laying the foundation for quantification of epithelial-mesenchymal heterogeneity and understanding the role of the intermediate EMT state in tumor progression.

E2F3 drives the epithelial-to-mesenchymal transition, cell invasion, and metastasis in breast cancer

2021 ◽  
pp. 153537022110356
Author(s):  
Shirley Jusino ◽  
Yainyrette Rivera-Rivera ◽  
Camille Chardón-Colón ◽  
Armando J Ruiz-Justiz ◽  
Jaleisha Vélez-Velázquez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Invasion ◽  
Epithelial To Mesenchymal Transition ◽  
Chromosome Instability ◽  
Metastatic Potential ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
Tumor Growth And Metastasis ◽  
And Migration

E2F3 is a transcription factor that may initiate tumorigenesis if overexpressed. Previously, we demonstrated that E2F3 mRNA is overexpressed in breast cancer and that E2F3 overexpression results in centrosome amplification and unregulated mitosis, which can promote aneuploidy and chromosome instability to initiate and sustain tumors. Further, we demonstrated that E2F3 leads to overexpression of the mitotic regulator Shugoshin-1, which until recently had unknown roles in cancer. This study aims to evaluate the roles of E2F3 and Shugoshin-1 in breast cancer metastatic potential. Here we demonstrated that E2F3 and Shugoshin-1 silencing leads to reduced cell invasion and migration in two mesenchymal triple-negative breast cancer (TNBC) cell lines (MDA-MB-231 and Hs578t). Moreover, E2F3 and Shugoshin-1 modulate the expression of epithelial-to-mesenchymal transition-associated genes such as Snail, E-Cadherin, and multiple matrix metalloproteinases. Furthermore, E2F3 depletion leads to reductions in tumor growth and metastasis in NOD- scid Gamma mice. Results from this study suggest a key role for E2F3 and a novel role for Shugoshin-1 in metastatic progression. These results can further help in the improvement of TNBC targeted therapies by interfering with pathways that intersect with the E2F3 and Shugoshin-1 signaling pathways.

scholarly journals Identification of TAZ-Dependent Breast Cancer Vulnerabilities Using a Chemical Genomics Screening Approach

2021 ◽  
Vol 9 ◽  
Author(s):  
He Shen ◽  
Yanmin Chen ◽  
Yin Wan ◽  
Tao Liu ◽  
Jianmin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Chemotherapeutic Agents ◽  
Binding Motif ◽  
Metastatic Progression ◽  
Tumor Seeding ◽  
Mesenchymal Transition

Breast cancer stem cells (BCSCs) represent a subpopulation of tumor cells that can self-renew and generate tumor heterogeneity. Targeting BCSCs may ameliorate therapy resistance, tumor growth, and metastatic progression. However, the origin and molecular mechanisms underlying their cellular properties are poorly understood. The transcriptional coactivator with PDZ-binding motif (TAZ) promotes mammary stem/progenitor cell (MaSC) expansion and maintenance but also confers stem-like traits to differentiated tumor cells. Here, we describe the rapid generation of experimentally induced BCSCs by TAZ-mediated reprogramming of human mammary epithelial cells, hence allowing for the direct analysis of BCSC phenotypes. Specifically, we establish genetically well-defined TAZ-dependent (TAZDEP) and -independent (TAZIND) cell lines with cancer stem cell (CSC) traits, such as self-renewal, variable resistance to chemotherapeutic agents, and tumor seeding potential. TAZDEP cells were associated with the epithelial to mesenchymal transition, embryonic, and MaSC signature genes. In contrast, TAZIND cells were characterized by a neuroendocrine transdifferentiation transcriptional program associated with Polycomb repressive complex 2 (PRC2). Mechanistically, we identify Cyclin D1 (CCND1) as a critical downstream effector for TAZ-driven tumorigenesis. Overall, our results reveal a critical TAZ-CCND1-CDK4/CDK6 signaling axis, suggesting novel therapeutic approaches to eliminate both BCSCs and therapy-resistant cancer cells.

scholarly journals Transforming Growth Factor-β Promotes Morphomechanical Effects Involved in Epithelial to Mesenchymal Transition in Living Hepatocellular Carcinoma

2018 ◽  
Vol 20 (1) ◽  
pp. 108 ◽  
Author(s):  
Mariafrancesca Cascione ◽  
Stefano Leporatti ◽  
Francesco Dituri ◽  
Gianluigi Giannelli
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Structural Characteristics ◽  
Biological Data ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Biomechanical Behavior

The epithelial mesenchymal transition (EMT) is a physiological multistep process involving epithelial cells acquiring a mesenchymal-like phenotype. It is widely demonstrated that EMT is linked to tumor progression and metastasis. The transforming growth factor (TGF)-β pathways have been widely investigated, but its role in the hepatocarcinoma EMT is still unclear. While the biochemical pathways have been extensively studied, the alteration of biomechanical behavior correlated to cellular phenotype and motility is not yet fully understood. To better define the involvement of TGF-β1 in the metastatic progression process in different hepatocarcinoma cell lines (HepG2, PLC/PRF/5, HLE), we applied a systematic morphomechanical approach in order to investigate the physical and the structural characteristics. In addition, we evaluated the antitumor effect of LY2157299, a TGF-βR1 kinase inhibitor, from a biomechanical point of view, using Atomic Force and Confocal Microscopy. Our approach allows for validation of biological data, therefore it may be used in the future as a diagnostic tool to be combined with conventional biomolecular techniques.

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