scholarly journals Deregulation of Transcriptional Enhancers in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3532
Author(s):  
Fatemeh Mirzadeh Azad ◽  
Yaser Atlasi
Keyword(s):  
Epigenetic Regulation ◽  
Adult Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Plasticity ◽  
Tumour Heterogeneity ◽  
Mesenchymal Transition ◽  
Transcriptional Enhancers ◽  
Control Gene Expression ◽  
Epigenetic Modifiers ◽  
External Cues

Epigenetic regulations can shape a cell’s identity by reversible modifications of the chromatin that ultimately control gene expression in response to internal and external cues. In this review, we first discuss the concept of cell plasticity in cancer, a process that is directly controlled by epigenetic mechanisms, with a particular focus on transcriptional enhancers as the cornerstone of epigenetic regulation. In the second part, we discuss mechanisms of enhancer deregulation in adult stem cells and epithelial-to-mesenchymal transition (EMT), as two paradigms of cell plasticity that are dependent on epigenetic regulation and serve as major sources of tumour heterogeneity. Finally, we review how genetic variations at enhancers and their epigenetic modifiers contribute to tumourigenesis, and we highlight examples of cancer drugs that target epigenetic modifications at enhancers.

scholarly journals OMRT-11. The effect of microenvironment on glioblastoma stem cells therapeutic resistance

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii9-ii9
Author(s):  
Tamara Lah Turnsek ◽  
Barbara Breznik ◽  
Bernarda Majc ◽  
Metka Novak ◽  
Andrej Porčnik ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Combined Treatment ◽  
Cell Plasticity ◽  
Glioblastoma Stem Cells ◽  
Mesenchymal Transition ◽  
Non Invasive ◽  
Differential Gene

Abstract Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process in physiologic processes and invasion of various types of carcinoma and glioblastoma (GBM) cells. EMT is activated and regulated by specific endogenous triggers in complex network of intercellular interactions and signaling pathways. The hallmark of cancer-linked EMT are intermediate states that show notable cell plasticity, characteristic of cancer stem cells (CSCs), including glioblastoma stem cells – GSCs. GSCs resistance to irradiation (IR) and temozolomide (TMZ) chemotherapy is responsible for early relapses, even at distant brain sites. As GSCs are mostly homing to their “niches” as slowly-dividing GSC-subtype, mimicking a proneural-like non- invasive phenotype PN-genotype, we assume that this, by undergoing an EMT-like transition, GSCs are-reprogrammed to an invasive mesenchymal (MES) GBs/GSCs phenotype in a processes, called PMT (1). However, it is not known, if and by which environmental cues within the niche, this transition of GSCs is induced in vivo. In this work, we are presenting the transriptome data obtained when we exposed GSC spheroids to irradiation alone, TMZ alone and to the combined treatment in vitro and compared their differential genetic fingerprints related to EMT/PMT transition to the GSCs PMT transition, when embedded in their natural microenvironment in the GBM organoid model. The differential gene expression upon GSCs therapeutic perturbation (when alone and vs in the tumoroid microenvironment) will reveal the effects of the major candidate genes, associated with micronevironmendt stromal cells and matrix are contributing their observed EMT/PMT transition of GSCs in vivo. •1. Majc, B., Sever, T., Zarić, M, Breznik, B., Turk, B, Lah Turnšek, T. Epithelial- to-mesenchymal transition as the driver of changing carcinoma and glioblastoma microenvironment. DOI: 10.1016/j.bbamcr.2020.118782

scholarly journals Cancer Stem Cell Plasticity – A Deadly Deal

2019 ◽  
Author(s):  
P. T. Archana ◽  
Saxena Kritika ◽  
Reshma Murali ◽  
Mohit Kumar Jolly ◽  
Radhika Nair
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Therapeutic Resistance ◽  
Extensive Investigation ◽  
Epigenetic Factors ◽  
Therapeutic Approaches ◽  
Cell Plasticity ◽  
Mesenchymal Transition ◽  
Recent Developments ◽  
High Level

Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

scholarly journals Contribution of Epithelial Plasticity to Therapy Resistance

2019 ◽  
Vol 8 (5) ◽  
pp. 676 ◽  
Author(s):  
Patricia G. Santamaría ◽  
Gema Moreno-Bueno ◽  
Amparo Cano
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Immune Therapy ◽  
Fatal Outcome ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Clinical Samples ◽  
Tumour Heterogeneity ◽  
Mesenchymal Transition ◽  
Epithelial Plasticity ◽  
Potential Link

Therapy resistance is responsible for tumour recurrence and represents one of the major challenges in present oncology. Significant advances have been made in the understanding of the mechanisms underlying resistance to conventional and targeted therapies improving the clinical management of relapsed patients. Unfortunately, in too many cases, resistance reappears leading to a fatal outcome. The recent introduction of immunotherapy regimes has provided an unprecedented success in the treatment of specific cancer types; however, a good percentage of patients do not respond to immune-based treatments or ultimately become resistant. Cellular plasticity, cancer cell stemness and tumour heterogeneity have emerged as important determinants of treatment resistance. Epithelial-to-mesenchymal transition (EMT) is associated with resistance in many different cellular and preclinical models, although little evidence derives directly from clinical samples. The recognition of the presence in tumours of intermediate hybrid epithelial/mesenchymal states as the most likely manifestation of epithelial plasticity and their potential link to stemness and tumour heterogeneity, provide new clues to understanding resistance and could be exploited in the search for anti-resistance strategies. Here, recent evidence linking EMT/epithelial plasticity to resistance against conventional, targeted and immune therapy are summarized. In addition, future perspectives for related clinical approaches are also discussed.

scholarly journals Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

2017 ◽  
Vol 247 (3) ◽  
pp. 481-491 ◽  
Author(s):  
Patricia Carvalho-cruz ◽  
Frederico Alisson-Silva ◽  
Adriane R. Todeschini ◽  
Wagner B. Dias
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Metabolic Changes ◽  
Cell Plasticity ◽  
Mesenchymal Transition

scholarly journals Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression

2021 ◽  
Author(s):  
Fabiana Lüönd ◽  
Stefanie Tiede ◽  
Gerhard Christofori
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumour Cell ◽  
Current Knowledge ◽  
Tumour Progression ◽  
Malignant Tumour ◽  
Cell Plasticity ◽  
Tumour Heterogeneity ◽  
Extrinsic Factors ◽  
Mesenchymal Transition

AbstractHeterogeneity within a tumour increases its ability to adapt to constantly changing constraints, but adversely affects a patient’s prognosis, therapy response and clinical outcome. Intratumoural heterogeneity results from a combination of extrinsic factors from the tumour microenvironment and intrinsic parameters from the cancer cells themselves, including their genetic, epigenetic and transcriptomic traits, their ability to proliferate, migrate and invade, and their stemness and plasticity attributes. Cell plasticity constitutes the ability of cancer cells to rapidly reprogramme their gene expression repertoire, to change their behaviour and identities, and to adapt to microenvironmental cues. These features also directly contribute to tumour heterogeneity and are critical for malignant tumour progression. In this article, we use breast cancer as an example of the origins of tumour heterogeneity (in particular, the mutational spectrum and clonal evolution of progressing tumours) and of tumour cell plasticity (in particular, that shown by tumour cells undergoing epithelial-to-mesenchymal transition), as well as considering interclonal cooperativity and cell plasticity as sources of cancer cell heterogeneity. We review current knowledge on the functional contribution of cell plasticity and tumour heterogeneity to malignant tumour progression, metastasis formation and therapy resistance.

scholarly journals Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiu-Luo Liu ◽  
Maochao Luo ◽  
Canhua Huang ◽  
Hai-Ning Chen ◽  
Zong-Guang Zhou
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Subsequent Transformation ◽  
Metastatic Cells

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.

Epigenetic regulation of TGF-β1 signalling in dilative aortopathy of the thoracic ascending aorta

2016 ◽  
Vol 130 (16) ◽  
pp. 1389-1405 ◽  
Author(s):  
Amalia Forte ◽  
Umberto Galderisi ◽  
Marilena Cipollaro ◽  
Marisa De Feo ◽  
Alessandro Della Corte
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β1 ◽  
Ascending Aorta ◽  
Mesenchymal Transition ◽  
Aorta Dilatation ◽  
Tgf Β1

The term ‘epigenetics’ refers to heritable, reversible DNA or histone modifications that affect gene expression without modifying the DNA sequence. Epigenetic modulation of gene expression also includes the RNA interference mechanism. Epigenetic regulation of gene expression is fundamental during development and throughout life, also playing a central role in disease progression. The transforming growth factor β1 (TGF-β1) and its downstream effectors are key players in tissue repair and fibrosis, extracellular matrix remodelling, inflammation, cell proliferation and migration. TGF-β1 can also induce cell switch in epithelial-to-mesenchymal transition, leading to myofibroblast transdifferentiation. Cellular pathways triggered by TGF-β1 in thoracic ascending aorta dilatation have relevant roles to play in remodelling of the vascular wall by virtue of their association with monogenic syndromes that implicate an aortic aneurysm, including Loeys–Dietz and Marfan's syndromes. Several studies and reviews have focused on the progression of aneurysms in the abdominal aorta, but research efforts are now increasingly being focused on pathogenic mechanisms of thoracic ascending aorta dilatation. The present review summarizes the most recent findings concerning the epigenetic regulation of effectors of TGF-β1 pathways, triggered by sporadic dilative aortopathy of the thoracic ascending aorta in the presence of a tricuspid or bicuspid aortic valve, a congenital malformation occurring in 0.5–2% of the general population. A more in-depth comprehension of the epigenetic alterations associated with TGF-β1 canonical and non-canonical pathways in dilatation of the ascending aorta could be helpful to clarify its pathogenesis, identify early potential biomarkers of disease, and, possibly, develop preventive and therapeutic strategies.

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