scholarly journals Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 428 ◽  
Author(s):  
József Dudás ◽  
Andrea Ladányi ◽  
Julia Ingruber ◽  
Teresa Bernadette Steinbichler ◽  
Herbert Riechelmann
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Protein Translation ◽  
Therapy Resistance ◽  
Mesenchymal Transition ◽  
Rna Molecules ◽  
Tumor Microenvironments ◽  
Micro Rnas

Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.

scholarly journals The Role of Circular RNAs in Keratinocyte Carcinomas

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4240
Author(s):  
Thomas Meyer ◽  
Michael Sand ◽  
Lutz Schmitz ◽  
Eggert Stockfleth
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
Rna Molecules ◽  
Factors Associated ◽  
New Therapeutic Approaches ◽  
Non Coding Rna ◽  
Micro Rnas ◽  
Pubmed Search

Keratinocyte carcinomas (KC) include basal cell carcinomas (BCC) and cutaneous squamous cell carcinomas (cSCC) and represents the most common cancer in Europe and North America. Both entities are characterized by a very high mutational burden, mainly UV signature mutations. Predominately mutated genes in BCC belong to the sonic hedgehog pathway, whereas, in cSCC, TP53, CDKN2A, NOTCH1/2 and others are most frequently mutated. In addition, the dysregulation of factors associated with epithelial to mesenchymal transition (EMT) was shown in invasive cSCC. The expression of factors associated with tumorigenesis can be controlled in several ways and include non-coding RNA molecules, such as micro RNAs (miRNA) long noncoding RNAs (lncRNA) and circular RNAs (circRNA). To update findings on circRNA in KC, we reviewed 13 papers published since 2016, identified in a PubMed search. In both BCC and cSCC, numerous circRNAs were identified that were differently expressed compared to healthy skin. Some of them were shown to target miRNAs that are also dysregulated in KC. Moreover, some studies confirmed the biological functions of individual circRNAs involved in cancer development. Thus, circRNAs may be used as biomarkers of disease and disease progression and represent potential targets of new therapeutic approaches for KC.

scholarly journals EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 312 ◽  
Author(s):  
Barbara Colella ◽  
Fiorella Faienza ◽  
Sabrina Di Bartolomeo
Keyword(s):  
Transcription Factors ◽  
Tumor Cells ◽  
Tissue Repair ◽  
Epithelial To Mesenchymal Transition ◽  
Signalling Pathways ◽  
Migration And Invasion ◽  
Cell Resistance ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
New Perspective

Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling pathways. Even though glial cells have a mesenchymal phenotype, an EMT-like process tends to exacerbate it during gliomagenesis and progression to more aggressive stages of the disease. Autophagy is an evolutionary conserved degradative process that cells use in order to maintain a proper homeostasis, and defects in autophagy have been associated to several pathologies including cancer. Besides modulating cell resistance or sensitivity to therapy, autophagy also affects the migration and invasion capabilities of tumor cells. Despite this evidence, few papers are present in literature about the involvement of autophagy in EMT-like processes in glioblastoma (GBM) so far. This review summarizes the current understanding of the interplay between autophagy and EMT in cancer, with special regard to GBM model. As the invasive behaviour is a hallmark of GBM aggressiveness, defining a new link between autophagy and EMT can open a novel scenario for targeting these processes in future therapeutical approaches.

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 Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2248 ◽  
Author(s):  
Kenneth Bruneel ◽  
Jeroen Verstappe ◽  
Niels Vandamme ◽  
Geert Berx
Keyword(s):  
Transcription Factors ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Resistant Cell ◽  
Cellular Plasticity ◽  
Mesenchymal Transition ◽  
Cell State ◽  
Promising Therapeutic Target ◽  
Main Driver ◽  
Mitf Expression

It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity.

PHENOTYPIC HETEROGENEITY IN DISSEMINATED PROSTATE CANCER TUMOR CELLS: IMPLICATIONS IN EPITHELIAL TO MESENCHYMAL TRANSITION

2009 ◽  
Vol 181 (4S) ◽  
pp. 756-756
Author(s):  
Theodore D Koreckij ◽  
Todd M Morgan ◽  
Paul H Lange ◽  
Ilsa Coleman ◽  
Roger Coleman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Phenotypic Heterogeneity ◽  
Mesenchymal Transition ◽  
Cancer Tumor

scholarly journals miR-204 Shifts the Epithelial to Mesenchymal Transition in Concert with the Transcription Factors RUNX2, ETS1, and cMYB in Prostate Cancer Cell Line Model

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Krassimira Todorova ◽  
Diana Zasheva ◽  
Kristiyan Kanev ◽  
Soren Hayrabedyan
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Cancer Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Mesenchymal Transition ◽  
Cell Line Model ◽  
E Cadherin

Epithelial to mesenchymal transition is an essential step in advanced cancer development. Many master transcription factors shift their expression to drive this process, while noncoding RNAs families like miR-200 are found to restrict it. In this study we investigated how the tumor suppressor miR-204 and several transcription factors modulate main markers of mesenchymal transformation like E- and N-cadherin, SLUG, VEGF, and SOX-9 in prostate cancer cell line model (LNCaP, PC3, VCaP, and NCI-H660). We found that SLUG, E-cadherin, and N-cadherin are differentially modulated by miR-204, using miR-204 specific mimics and inhibitors and siRNA gene silencing (RUNX2, ETS-1, and cMYB). The genome perturbation associated TMPRSS2-ERG fusion coincided with shift from tumor-suppressor to tumor-promoting activity of this miRNA. The ability of miR-204 to suppress cancer cell viability and migration was lost in the fusion harboring cell lines. We found differential E-cadherin splicing corroborating to miR-204 modulatory effects. RUNX2, ETS1, and cMYB are involved in the regulation of E-cadherin, N-cadherin, and VEGFA expression. RUNX2 knockdown results in SOX9 downregulation, while ETS1 and cMYB silencing result in SOX9 upregulation in VCaP cells. Their expression was found to be also methylation dependent. Our study provides means for understanding cancer heterogeneity in regard to adapted therapeutic approaches development.

Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

2021 ◽  
Vol 21 ◽  
Author(s):  
Kenneth Omabe ◽  
Sandra Uduituma ◽  
David Igwe ◽  
Maxwell Omabe
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Epithelial To Mesenchymal Transition ◽  
Dna Damage Repair ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Cellular Reprogramming ◽  
Repair System ◽  
Mesenchymal Transition ◽  
Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

scholarly journals Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

2019 ◽  
Vol 116 (6) ◽  
pp. 2237-2242 ◽  
Author(s):  
Eva A. Ebbing ◽  
Amber P. van der Zalm ◽  
Anne Steins ◽  
Aafke Creemers ◽  
Simone Hermsen ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Treatment Resistance ◽  
Serum Levels ◽  
Therapy Resistance ◽  
Mesenchymal Transition ◽  
Dismal Prognosis ◽  
Organoid Cultures

Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.

Sign in / Sign up

Export Citation Format

Share Document