scholarly journals Every Beat You Take—The Wilms′ Tumor Suppressor WT1 and the Heart

2021 ◽  
Vol 22 (14) ◽  
pp. 7675
Author(s):  
Nicole Wagner ◽  
Kay-Dietrich Wagner
Keyword(s):  
Tumor Suppressor ◽  
Heart Development ◽  
Epithelial Mesenchymal Transition ◽  
Cardiac Development ◽  
Wilms Tumor ◽  
Current Knowledge ◽  
Adult Life ◽  
Autonomous Nervous System ◽  
Mesenchymal Transition ◽  
Organ Systems

Nearly three decades ago, the Wilms’ tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review summarizes the results from many research groups which allowed to establish a relevant function for Wt1 in cardiac development and disease. During development, Wt1 is involved in fundamental processes as the formation of the epicardium, epicardial epithelial-mesenchymal transition, coronary vessel development, valve formation, organization of the cardiac autonomous nervous system, and formation of the cardiac ventricles. Wt1 is further implicated in cardiac disease and repair in adult life. We summarize here the current knowledge about expression and function of Wt1 in heart development and disease and point out controversies to further stimulate additional research in the areas of cardiac development and pathophysiology. As re-activation of developmental programs is considered as paradigm for regeneration in response to injury, understanding of these processes and the molecules involved therein is essential for the development of therapeutic strategies, which we discuss on the example of WT1.

The multiple functions of the proepicardial/epicardial cell lineage in heart development

2018 ◽  
Author(s):  
Robert Dettman ◽  
Juan Antonio Guadix ◽  
Elena Cano ◽  
Rita Carmona ◽  
Ramón Muñoz-Chápuli
Keyword(s):  
Heart Development ◽  
Epithelial Mesenchymal Transition ◽  
Cardiac Development ◽  
Cell Layer ◽  
Cell Lineage ◽  
Outer Cell ◽  
Mesenchymal Transition ◽  
Myocardial Development ◽  
Epicardial Cell ◽  
Outer Cell Layer

The epicardium is the outer cell layer of the vertebrate heart. In recent years, both the embryonic and adult epicardium have revealed unsuspected peculiarities and functions, which are essential for cardiac development. In this chapter we review the current literature on the epicardium, and describe its evolutionary origin, the mechanisms leading to the induction of its extracardiac progenitor tissue, the proepicardium, and the way in which the proepicardium is transferred to the heart to form the epicardium. We also describe the epicardial epithelial–mesenchymal transition from which mesenchymal cells originate, and the developmental fate of these cells, which contribute to the vascular, interstitial, valvular, and adipose tissue. Finally, we review the molecular interactions established between the epicardium and the myocardium, which are key for myocardial development and can also play a role in cardiac homeostasis. This chapter highlights how the epicardium has become a major protagonist in cardiac biology.

Wt1-expressing progenitors contribute to multiple tissues in the developing lung

2013 ◽  
Vol 305 (4) ◽  
pp. L322-L332 ◽  
Author(s):  
Elena Cano ◽  
Rita Carmona ◽  
Ramón Muñoz-Chápuli
Keyword(s):  
Smooth Muscle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Fluorescent Protein ◽  
Wilms Tumor ◽  
Yellow Fluorescent Protein ◽  
Suppressor Gene ◽  
Differentiation Potential ◽  
Mesenchymal Transition ◽  
Lung Morphogenesis

Lungs develop from paired endodermal outgrowths surrounded by a mesodermal mesenchyme. Part of this mesenchyme arises from epithelial-mesenchymal transition of the mesothelium that lines the pulmonary buds. Previous studies have shown that this mesothelium-derived mesenchyme contributes to the smooth muscle of the pulmonary vessels, but its significance for lung morphogenesis and its developmental fate are still little known. We have studied this issue using the transgenic mouse model mWt1/IRES/GFP-Cre (Wt1cre) crossed with the Rosa26R-EYFP reporter mouse. In the developing lungs, Wt1, the Wilms' tumor suppressor gene, is specifically expressed in the embryonic mesothelium. In the embryos obtained from the crossbreeding, the Wt1-expressing cell lineage produces the yellow fluorescent protein (YFP), allowing for colocalization with differentiation markers. Wt1cre-YFP cells were very abundant from the origin of the lung buds to postnatal stages, contributing significantly to pulmonary endothelial and smooth muscle cells, bronchial musculature, tracheal and bronchial cartilage, as well as CD34+ fibroblast-like interstitial cells. Thus Wt1cre-YFP mesenchymal cells show the very same differentiation potential as the splanchnopleural mesenchyme surrounding the lung buds. FSP1+ fibroblast-like cells were always YFP−; they expressed the common leukocyte antigen CD45 and were apparently recruited from circulating progenitors. We have also found defects in pulmonary development in Wt1−/− embryos, which showed abnormally fused lung lobes, round-shaped and reduced pleural cavities, and diaphragmatic hernia. Our results suggest a novel role for the embryonic mesothelium-derived cells in lung morphogenesis and involve the Wilms' tumor suppressor gene in the development of this organ.

Adenomyosis – its possible effect on endometrial function and receptivity

2021 ◽  
Vol 86 (3) ◽  
pp. 205-209
Author(s):  
Karel Crha ◽  
◽  
Michal Ješeta ◽  
Radovan Pilka ◽  
Pavel Ventruba ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Histopathological Examination ◽  
Transvaginal Ultrasound ◽  
Embryo Implantation ◽  
Diagnostic Methods ◽  
Mesenchymal Transition ◽  
New Information

Summary Objective: There have been many studies on adenomyosis, which can impair the quality of life of a woman. There are various kinds of opinions on the pathogenesis, diagnostics and treatment of adenomyosis. The goal of this article is to present the current knowledge of adenomyosis and its impact on the endometrial function and receptivity. Methods: PubMed/Medline, Web of Sciences and Scopus were searched for the articles in English indexed until February 2021 with terms of: adenomyosis, endometrial receptivity, and infertility. Results: Recent studies on angiogenesis and epithelial-mesenchymal transition in the endometrium bring new information on the ethiology and pathogenesis of adenomyosis. In clinical practice, the main diagnostic methods of adenomyosis include transvaginal ultrasound, magnetic resonance imaging or hysteroscopy, although the definitive confirmation is set by histopathological examination. The rules of #Enzian classification of endometriosis should be applied for the classification of adenomyosis. The treatment of adenomyosis should consider individual clinical presentation and reproductive plans of a patient and should be performed in centers for the treatment of endometriosis. Conclusion: Adenomyosis affects endometrial vascularisation and epithelial-mesenchymal transition/mesenchymal-epithelial transition; thus, it can be the cause of irregular uterine bleeding or embryo implantation failure. The research and analysis of endometrial proteome could lead to the new ways of adenomyosis treatment.

scholarly journals RUNX1 suppresses breast cancer stemness and tumor growth

2018 ◽  
Author(s):  
Deli Hong ◽  
Andrew J. Fritz ◽  
Kristiaan H. Finstad ◽  
Mark P. Fitzgerald ◽  
Adam L. Viens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Cancer Stem Cell ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Cell Activity ◽  
Mesenchymal Transition

SummaryRecent studies have revealed that mutations in the transcription factor Runx1 are prevalent in breast tumors. Yet, how loss of Runx1 contributes to breast cancer (BCa) remains unresolved. We demonstrate for the first time that Runx1 represses the breast cancer stem cell (BCSC) phenotype and consequently, functions as a tumor suppressor in breast cancer. Runx1 ectopic expression in MCF10AT1 and MCF10CA1a BCa cells reduces (60%) migration, invasion and in vivo tumor growth in mouse mammary fat pad (P<0.05). Runx1 is decreased in BCSCs, and overexpression of Runx1 suppresses tumorsphere formation and reduces the BCSC population. Furthermore, Runx1 inhibits Zeb1 expression, while Runx1 depletion activates Zeb1 and the epithelial-mesenchymal transition. Mechanistically Runx1 functions as a tumor suppressor in breast cancer through repression of cancer stem cell activity. This key regulation of BCSCs by Runx1 may be shared in other epithelial carcinomas, highlighting the importance of Runx1 in solid tumors.

scholarly journals Pathways to Breast Cancer Recurrence

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Aamir Ahmad
Keyword(s):  
Breast Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Recurrent Disease ◽  
Current Knowledge ◽  
Cancer Recurrence ◽  
Breast Cancer Recurrence ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Number Of Factors ◽  
Prevention Of Breast Cancer

Breast cancer remains a deadly disease, even with all the recent technological advancements. Early intervention has made an impact, but an overwhelmingly large number of breast cancer patients still live under the fear of “recurrent” disease. Breast cancer recurrence is clinically a huge problem and one that is largely not well understood. Over the years, a number of factors have been studied with an overarching aim of being able to prognose recurrent disease. This paper attempts to provide an overview of our current knowledge of breast cancer recurrence and its associated challenges. Through a survey of the literature on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), various signaling pathways such as Notch/Wnt/hedgehog, and microRNAs (miRNAs), we also examine the hypotheses that are currently under investigation for the prevention of breast cancer recurrence.

scholarly journals Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 7 ◽  
Author(s):  
Chih-Ming Huang ◽  
Chin-Sheng Huang ◽  
Tung-Nien Hsu ◽  
Mao-Suan Huang ◽  
Iat-Hang Fong ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Survival Rate ◽  
Tumor Suppressor ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Regulatory Element ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
E Cadherin

Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

scholarly journals TrkB-Induced Inhibition of R-SMAD/SMAD4 Activation is Essential for TGF-β-Mediated Tumor Suppressor Activity

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1048
Author(s):  
Min Soo Kim ◽  
Wook Jin
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathway ◽  
Tumor Suppression ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Potential ◽  
Suppressor Activity ◽  
Mesenchymal Transition ◽  
Stat3 Signaling Pathway ◽  
Tumor Suppressor Activity

TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial–mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-β-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-β signaling pathway as it inhibits the TGF-β-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-β-mediated R-SMAD/SMAD4 complex formation and suppress TGF-β-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-β signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-β tumor suppressor activity in cancer cells.

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