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TGF-beta Family in Fibrosis and Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2017) | Viewed by 103808

Special Issue Editor

1. TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de l'Hospitalet, 199, L'Hospitalet, 08908 Barcelona, Spain
2. Oncology Program, CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
3. Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain
Interests: liver; TGF-beta; EGF; NADPH oxidases; NOX4; oxidative stress; epithelial mesenchymal transition (EMT); liver stem cells; metabolism and liver; liver cancer; HCC; liver fibrosis; liver signaling
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Special Issue Information

Dear Colleagues,

The transforming growth factor (TGF)-beta family plays essential roles in the regulation of different cellular processes (including proliferation, differentiation, migration, or cell death), which are essential for the homeostasis of tissues and organs. Due to the diverse and pleiotropic TGF-β functions, de-regulation of its pathways contributes to human diseases. TGF-β is a pro-fibrotic factor in different tissues, such as lung, kidney, or liver. During tumorigenesis, TGF-β may behave as a suppressor factor at early stages; however, strong evidence suggests that overactivation of its signaling could later contribute to tumour progression, once cells escape from its cytostatic effects. For these reasons, targeting the TGF-β signaling pathway is being explored as a therapeutic tool for human fibrosis and cancer.

In this Special Issue, we aim to shed light on the state-of-the-art, as well as novel data, that contribute to increasing our knowledge regarding the role of the TGF-β family in the progression of human pathologies, with particular emphasis in fibrosis and cancer. To this end, we welcome experts in the field to contribute research papers and critical reviews on the various facets of TGF-β regulation and signaling that contribute to fibrosis and/or cancer, as well as how inhibitors of the TGF-β pathway may be used as therapeutic tools for these diseases.

Dr. Isabel Fabregat
Guest Editor

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Keywords

  • TGF-beta
  • fibrosis
  • cancer

Published Papers (13 papers)

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Research

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16 pages, 3052 KiB  
Article
Fenofibrate Reduces the Asthma-Related Fibroblast-To-Myofibroblast Transition by TGF-Β/Smad2/3 Signaling Attenuation and Connexin 43-Dependent Phenotype Destabilization
by Milena Paw, Dawid Wnuk, Dominika Kądziołka, Aleksandra Sęk, Sławomir Lasota, Jarosław Czyż, Zbigniew Madeja and Marta Michalik
Int. J. Mol. Sci. 2018, 19(9), 2571; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092571 - 29 Aug 2018
Cited by 24 | Viewed by 4088
Abstract
The activation of human bronchial fibroblasts by transforming growth factor-β1 (TGF-β1) leads to the formation of highly contractile myofibroblasts in the process of the fibroblast–myofibroblast transition (FMT). This process is crucial for subepithelial fibrosis and bronchial wall remodeling in asthma. [...] Read more.
The activation of human bronchial fibroblasts by transforming growth factor-β1 (TGF-β1) leads to the formation of highly contractile myofibroblasts in the process of the fibroblast–myofibroblast transition (FMT). This process is crucial for subepithelial fibrosis and bronchial wall remodeling in asthma. However, this process evades current therapeutic asthma treatment strategies. Since our previous studies showed the attenuation of the TGF-β1-induced FMT in response to lipid-lowering agents (e.g., statins), we were interested to see whether a corresponding effect could be obtained upon administration of hypolipidemic agents. In this study, we investigated the effect of fenofibrate on FMT efficiency in populations of bronchial fibroblasts derived from asthmatic patients. Fenofibrate exerted a dose-dependent inhibitory effect on the FMT, even though it did not efficiently affect the expression of α-smooth muscle actin (α-SMA; marker of myofibroblasts); however, it considerably reduced its incorporation into stress fibers through connexin 43 regulation. This effect was accompanied by disturbances in the actin cytoskeleton architecture, impairments in the maturation of focal adhesions, and the fenofibrate-induced deactivation of TGF-β1/Smad2/3 signaling. These data suggest that fenofibrate interferes with myofibroblastic differentiation during asthma-related subepithelial fibrosis. The data indicate the potential application of fenofibrate in the therapy and prevention of bronchial remodeling during the asthmatic process. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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2793 KiB  
Article
The Role of PAR2 in TGF-β1-Induced ERK Activation and Cell Motility
by Hendrik Ungefroren, David Witte, Christian Fiedler, Thomas Gädeken, Roland Kaufmann, Hendrik Lehnert, Frank Gieseler and Bernhard H. Rauch
Int. J. Mol. Sci. 2017, 18(12), 2776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122776 - 20 Dec 2017
Cited by 19 | Viewed by 5665
Abstract
Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular [...] Read more.
Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular signal-regulated kinase (ERK) signaling) is required for cell migration and whether it is also dependent on PAR2. Methods: RNA interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation to detect a PAR2–ALK5 physical interaction. Results: Inhibition of ERK signaling with the MEK inhibitor U0126 blunted the ability of TGF-β1 to induce migration in pancreatic cancer Panc1 cells. ERK activation in response to PAR2 agonistic peptide (PAR2–AP) was strong and rapid, while it was moderate and delayed in response to TGF-β1. Basal and TGF-β1-dependent ERK, but not SMAD activation, was blocked by U0126 in Panc1 and other cell types indicating that ERK activation is downstream or independent of SMAD signaling. Moreover, cellular depletion of PAR2 in HaCaT cells strongly inhibited TGF-β1-induced ERK activation, while the biased PAR2 agonist GB88 at 10 and 100 µM potentiated TGF-β1-dependent ERK activation and cell migration. Finally, we provide evidence for a physical interaction between PAR2 and ALK5. Our data show that both PAR2–AP- and TGF-β1-induced cell migration depend on ERK activation, that PAR2 expression is crucial for TGF-β1-induced ERK activation, and that the functional cooperation of PAR2 and TGF-β1 involves a physical interaction between PAR2 and ALK5. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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3355 KiB  
Article
Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-β1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt
by Alícia Giménez, Paula Duch, Marta Puig, Marta Gabasa, Antoni Xaubet and Jordi Alcaraz
Int. J. Mol. Sci. 2017, 18(11), 2431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112431 - 16 Nov 2017
Cited by 55 | Viewed by 6361
Abstract
Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-β1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-β1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-β1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-β1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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4145 KiB  
Article
Endothelial Mesenchymal Transition in Hypoxic Microvascular Endothelial Cells and Paracrine Induction of Cardiomyocyte Apoptosis Are Mediated via TGFβ1/SMAD Signaling
by Isabella Sniegon, Mona Prieß, Jacqueline Heger, Rainer Schulz and Gerhild Euler
Int. J. Mol. Sci. 2017, 18(11), 2290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112290 - 31 Oct 2017
Cited by 29 | Viewed by 5769
Abstract
Cardiac remodeling plays a crucial role in the development of heart failure after mycocardial infarction. Besides cardiomyocytes, endothelial cells are recognized to contribute to cardiac remodeling. We now investigated processes of endothelial mesenchymal transition (EndoMT) in microvascular endothelial cells of rat (MVEC) under [...] Read more.
Cardiac remodeling plays a crucial role in the development of heart failure after mycocardial infarction. Besides cardiomyocytes, endothelial cells are recognized to contribute to cardiac remodeling. We now investigated processes of endothelial mesenchymal transition (EndoMT) in microvascular endothelial cells of rat (MVEC) under hypoxia and paracrine effects on ventricular cardiomyocytes of adult rat. Exposure of MVECs to hypoxia/reoxygenation enhanced TGFβ/SMAD signaling, since phosphorylation, and thus activation, of SMAD1/5 and SMAD2 increased. This increase was blocked by inhibitors of TGFβ receptor types ALK1 or ALK5. Exposure of ventricular cardiomyocytes to conditioned medium from hypoxic/reoxygenated MVECs enhanced SMAD2 phosphorylation and provoked apoptosis in cardiomyoyctes. Both were blocked by ALK5 inhibition. To analyze autocrine effects of hypoxic TGFβ signaling we investigated EndoMT in MVECs. After 3 days of hypoxia the mesenchymal marker protein α-smooth muscle actin (α-SMA), and the number of α-SMA- and fibroblast specific protein 1 (FSP1)-positive cells increased in MVECs cultures. This was blocked by ALK5 inhibition. Similarly, TGFβ1 provoked enhanced expression of α-SMA and FSP1 in MVECs. In conclusion, hypoxia provokes EndoMT in MVECs via TGFβ1/SMAD2 signaling. Furthermore, release of TGFβ1 from MVECs acts in a paracrine loop on cardiomyocytes and provokes apoptotic death. Thus, in myocardial infarction hypoxic endothelial cells may contribute to cardiac remodeling and heart failure progression by promotion of cardiac fibrosis and cardiomyocytes death. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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4262 KiB  
Article
Transforming Growth Factor-β Drives the Transendothelial Migration of Hepatocellular Carcinoma Cells
by Petra Koudelkova, Victor Costina, Gerhard Weber, Steven Dooley, Peter Findeisen, Peter Winter, Rahul Agarwal, Karin Schlangen and Wolfgang Mikulits
Int. J. Mol. Sci. 2017, 18(10), 2119; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102119 - 10 Oct 2017
Cited by 15 | Viewed by 5834
Abstract
The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic [...] Read more.
The entry of malignant hepatocytes into blood vessels is a key step in the dissemination and metastasis of hepatocellular carcinoma (HCC). The identification of molecular mechanisms involved in the transmigration of malignant hepatocytes through the endothelial barrier is of high relevance for therapeutic intervention and metastasis prevention. In this study, we employed a model of hepatocellular transmigration that mimics vascular invasion using hepatic sinusoidal endothelial cells and malignant hepatocytes evincing a mesenchymal-like, invasive phenotype by transforming growth factor (TGF)-β. Labelling of respective cell populations with various stable isotopes and subsequent mass spectrometry analyses allowed the “real-time” detection of molecular changes in both transmigrating hepatocytes and endothelial cells. Interestingly, the proteome profiling revealed 36 and 559 regulated proteins in hepatocytes and endothelial cells, respectively, indicating significant changes during active transmigration that mostly depends on cell–cell interaction rather than on TGF-β alone. Importantly, matching these in vitro findings with HCC patient data revealed a panel of common molecular alterations including peroxiredoxin-3, epoxide hydrolase, transgelin-2 and collectin 12 that are clinically relevant for the patient’s survival. We conclude that hepatocellular plasticity induced by TGF-β is crucially involved in blood vessel invasion of HCC cells. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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2417 KiB  
Article
A Central Bioactive Region of LTBP-2 Stimulates the Expression of TGF-β1 in Fibroblasts via Akt and p38 Signalling Pathways
by Mohamed A. Sideek, Joshua Smith, Clementine Menz, Julian R. J. Adams, Allison J. Cowin and Mark A. Gibson
Int. J. Mol. Sci. 2017, 18(10), 2114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102114 - 09 Oct 2017
Cited by 15 | Viewed by 6273
Abstract
Latent transforming growth factor-β-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-β1 (TGF-β1) but appears to be implicated in the regulation of TGF-β1 bioactivity, although the mechanisms are largely [...] Read more.
Latent transforming growth factor-β-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-β1 (TGF-β1) but appears to be implicated in the regulation of TGF-β1 bioactivity, although the mechanisms are largely unknown. In experiments originally designed to study the displacement of latent TGF-β1 complexes from matrix storage, we found that the addition of exogenous LTBP-2 to cultured human MSU-1.1 fibroblasts caused an increase in TGF-β1 levels in the medium. However, the TGF-β1 increase was due to an upregulation of TGF-β1 expression and secretion rather than a displacement of matrix-stored TGF-β1. The secreted TGF-β1 was mainly in an inactive form, and its concentration peaked around 15 h after addition of LTBP-2. Using a series of recombinant LTBP-2 fragments, the bioactivity was identified to a small region of LTBP-2 consisting of an 8-Cys motif flanked by four epidermal growth factor (EGF)-like repeats. The LTBP-2 stimulation of TGF-β expression involved the phosphorylation of both Akt and p38 mitogen-activated protein kinase (MAPK) signalling proteins, and specific inactivation of each protein individually blocked TGF-β1 increase. The search for the cell surface receptor mediating this LTBP-2 activity proved inconclusive. Inhibitory antibodies to integrins β1 and αVβ5 showed no reduction of LTBP-2 stimulation of TGF-β1. However, TGF-β1 upregulation was partially inhibited by anti-αVβ3 integrin antibodies, suggestive of a direct or indirect role for this integrin. Overall, the study indicates that LTBP-2 can directly upregulate cellular TGF-β1 expression and secretion by interaction with cells via a short central bioactive region. This may be significant in connective tissue disorders involving aberrant TGF-β1 signalling. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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2098 KiB  
Article
Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine
by David Capper, Andreas Von Deimling, Alba A. Brandes, Antoine F. Carpentier, Santosh Kesari, Juan M. Sepulveda-Sanchez, Helen R. Wheeler, Olivier Chinot, Lawrence Cher, Joachim P. Steinbach, Pol Specenier, Jordi Rodon, Ann Cleverly, Claire Smith, Ivelina Gueorguieva, Colin Miles, Susan C. Guba, Durisala Desaiah, Shawn T. Estrem, Michael M. Lahn and Wolfgang Wickadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2017, 18(5), 995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18050995 - 06 May 2017
Cited by 24 | Viewed by 5533
Abstract
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was [...] Read more.
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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Review

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24 pages, 1319 KiB  
Review
TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer
by Laia Caja, Francesco Dituri, Serena Mancarella, Daniel Caballero-Diaz, Aristidis Moustakas, Gianluigi Giannelli and Isabel Fabregat
Int. J. Mol. Sci. 2018, 19(5), 1294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051294 - 26 Apr 2018
Cited by 220 | Viewed by 12833
Abstract
Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in [...] Read more.
Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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1856 KiB  
Review
BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration
by Blanca Herrera, Annalisa Addante and Aránzazu Sánchez
Int. J. Mol. Sci. 2018, 19(1), 39; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010039 - 23 Dec 2017
Cited by 46 | Viewed by 10645
Abstract
Bone Morphogenetic Proteins (BMPs) belong to the Transforming Growth Factor-β (TGF-β) family. Initially identified due to their ability to induce bone formation, they are now known to have multiple functions in a variety of tissues, being critical not only during development for tissue [...] Read more.
Bone Morphogenetic Proteins (BMPs) belong to the Transforming Growth Factor-β (TGF-β) family. Initially identified due to their ability to induce bone formation, they are now known to have multiple functions in a variety of tissues, being critical not only during development for tissue morphogenesis and organogenesis but also during adult tissue homeostasis. This review focus on the liver as a target tissue for BMPs actions, devoting most efforts to summarize our knowledge on their recently recognized and/or emerging roles on regulation of the liver regenerative response to various insults, either acute or chronic and their effects on development and progression of liver fibrosis in different pathological conditions. In an attempt to provide the basis for guiding research efforts in this field both the more solid and more controversial areas of research were highlighted. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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819 KiB  
Review
Role of MicroRNAs in TGF-β Signaling Pathway-Mediated Pulmonary Fibrosis
by Hara Kang
Int. J. Mol. Sci. 2017, 18(12), 2527; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122527 - 25 Nov 2017
Cited by 73 | Viewed by 8968
Abstract
Pulmonary fibrosis is the most common form of interstitial lung disease. The transforming growth factor-β (TGF-β) signaling pathway is extensively involved in the development of pulmonary fibrosis by inducing cell differentiation, migration, invasion, or hyperplastic changes. Accumulating evidence indicates that microRNAs (miRNAs) are [...] Read more.
Pulmonary fibrosis is the most common form of interstitial lung disease. The transforming growth factor-β (TGF-β) signaling pathway is extensively involved in the development of pulmonary fibrosis by inducing cell differentiation, migration, invasion, or hyperplastic changes. Accumulating evidence indicates that microRNAs (miRNAs) are dysregulated during the initiation of pulmonary fibrosis. miRNAs are small noncoding RNAs functioning as negative regulators of gene expression at the post-transcriptional level. A number of miRNAs have been reported to regulate the TGF-β signaling pathway and consequently affect the process of pulmonary fibrosis. A better understanding of the pro-fibrotic role of the TGF-β signaling pathway and relevant miRNA regulation will shed light on biomedical research of pulmonary fibrosis. This review summarizes the current knowledge of miRNAs regulating the TGF-β signaling pathway with relevance to pulmonary fibrosis. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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1305 KiB  
Review
Role of Transforming Growth Factor β in Uterine Fibroid Biology
by Michał Ciebiera, Marta Włodarczyk, Małgorzata Wrzosek, Błażej Męczekalski, Grażyna Nowicka, Krzysztof Łukaszuk, Magdalena Ciebiera, Aneta Słabuszewska-Jóźwiak and Grzegorz Jakiel
Int. J. Mol. Sci. 2017, 18(11), 2435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18112435 - 17 Nov 2017
Cited by 68 | Viewed by 8190
Abstract
Uterine fibroids (UFs) are benign tumors of the female genital tract made of the smooth muscle of the uterus. UF growth depends mostly on the influence of the steroid hormones and selected growth factors. Transforming growth factor β (TGF-βs) is a polypeptide that [...] Read more.
Uterine fibroids (UFs) are benign tumors of the female genital tract made of the smooth muscle of the uterus. UF growth depends mostly on the influence of the steroid hormones and selected growth factors. Transforming growth factor β (TGF-βs) is a polypeptide that consists of three isoforms: TGF-β1, TGF-β2, and TGF-β3. At present, TGF-β is considered to be one of the key factors in the pathophysiology of UFs. It plays a major role in cellular migration within the tumor, stimulates tumor growth, and enhances tumor metabolism. As a consequence of various dependencies, the synthesis and release of TGF-β in a UF tumor is increased, which results in excessive extracellular matrix production and storage. High concentrations or overexpression of TGF-β mediators may be responsible for clinically symptomatic UFs. The aim of this review was to check the available evidence for the influence of the TGF-β family on UF biology. We conducted their search in PubMed of the National Library of Medicine with the use of the following selected keywords: “uterine fibroid”, “leiomyoma”, and “transforming growth factor β”. After reviewing the titles and abstracts, more than 115 full articles were evaluated. We focused on the TGF-β-related molecular aspects and their influence on the most common symptoms that are associated with UFs. Also, we described how the available data might implicate the current medical management of UFs. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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2273 KiB  
Review
TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases
by Evangelia Pardali, Gonzalo Sanchez-Duffhues, Maria Catalina Gomez-Puerto and Peter Ten Dijke
Int. J. Mol. Sci. 2017, 18(10), 2157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102157 - 17 Oct 2017
Cited by 260 | Viewed by 16782
Abstract
Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as the cells responsible for the progression of the fibrotic process, and they originate from several sources, including [...] Read more.
Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as the cells responsible for the progression of the fibrotic process, and they originate from several sources, including quiescent tissue fibroblasts, circulating CD34+ fibrocytes and the phenotypic conversion of various cell types into activated myofibroblasts. Several studies have demonstrated that endothelial cells can transdifferentiate into mesenchymal cells through a process termed endothelial- mesenchymal transition (EndMT) and that this can give rise to activated myofibroblasts involved in the development of fibrotic diseases. Transforming growth factor β (TGF-β) has a central role in fibrogenesis by modulating the fibroblast phenotype and function, inducing myofibroblast transdifferentiation and promoting matrix accumulation. In addition, TGF-β by inducing EndMT may further contribute to the development of fibrosis. Despite extensive investigation of the pathogenesis of fibrotic diseases, no effective treatment strategies are available. Delineation of the mechanisms responsible for initiation and progression of fibrotic diseases is crucial for the development of therapeutic strategies for the treatment of the disease. In this review, we summarize the role of the TGF-β signaling pathway and EndMT in the development of fibrotic diseases and discuss their therapeutic potential. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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624 KiB  
Review
TGFβ Controls Ovarian Cancer Cell Proliferation
by Elisenda Alsina-Sanchís, Agnès Figueras, Alvaro Lahiguera, Marta Gil-Martín, Beatriz Pardo, Josep M. Piulats, Lola Martí, Jordi Ponce, Xavier Matias-Guiu, August Vidal, Alberto Villanueva and Francesc Viñals
Int. J. Mol. Sci. 2017, 18(8), 1658; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18081658 - 30 Jul 2017
Cited by 23 | Viewed by 4894
Abstract
There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these [...] Read more.
There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these tumors, research to elucidate the signaling pathways involved is required. The Transforming Growth Factor (TGFβ) family controls different cellular responses in development and cell homeostasis. Disruption of TGFβ signaling has been implicated in many cancers, including ovarian cancer. This article considers the involvement of TGFβ in ovarian cancer progression, and reviews the various mechanisms that enable the TGFβ signaling pathway to control ovarian cancer cell proliferation. These mechanistic explanations support the therapeutic use of TGFβ inhibitors in ovarian cancer, which are currently in the early phases of development. Full article
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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