TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts

Caraci, Filippo; Gili, Elisa; Calafiore, Marco; Failla, Marco; Rosa, Cristina La; Crimi, Nunzio; Sortino, Maria Angela; Nicoletti, Ferdinando; Copani, Agata; Vancheri, Carlo

doi:10.1016/j.phrs.2008.02.001

Cited by 190 publications

(152 citation statements)

References 41 publications

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“…Fibrotic lungs from animals lacking VEGF in myeloid cells show elevated levels of nuclear β-catenin and cyclin D1, a major downstream component of the Wnt/β-catenin signaling pathway (27), indicating increased Wnt/β-catenin signaling. It has been reported that Wnt/β-catenin signaling can be triggered by hypoxia in an HIF-dependent manner (13,14) and that the Wnt/ β-catenin pathway is involved in the regulation of pulmonary fibroblast proliferation and differentiation of myofibroblasts (5,(16)(17)(18). In agreement with these results, we observed increased numbers of myofibroblasts in fibrotic lungs from Mut animals.…”

Section: Discussionsupporting

confidence: 91%

“…Among various signaling pathways that are involved in the development of pulmonary fibrosis, the Wnt/ β-catenin pathway has been determined to be of major importance; it is linked to crucial fibrotic processes, including proliferation of pulmonary fibroblasts and their differentiation into myofibroblasts (5,(16)(17)(18). It has also been reported that Wnt/ β-catenin signaling can be triggered by hypoxia in an HIFdependent manner (13,14).…”

Section: Expression Of Hifs and Hypoxia Markers Is Elevated In Lungs mentioning

confidence: 99%

“…It has been shown in vitro that chronic hypoxia is a strong stimulus for collagen synthesis (8,9), and many genes involved in the remodeling of extracellular matrix and epithelial-to-mesenchymal transition are known HIF target genes (10); in turn, HIFs have been suggested to be involved in the development of tissue fibrosis (11). Besides the regulation of genes involved in angiogenesis, oxygen transport, and glucose metabolism (12), hypoxia and HIFs have been shown to affect Wnt/ β-catenin signaling (13,14), and the canonical Wnt/β-catenin pathway regulates crucial processes like fibroblast proliferation, myofibroblast differentiation, and epithelial-to-mesenchymal transformation, and is therefore a major pathway in the development of tissue fibrosis (5,(15)(16)(17)(18).…”

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confidence: 99%

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Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Stockmann

Kerdiles

Nomaksteinsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/β-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.

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Section: Discussionsupporting

confidence: 91%

Section: Expression Of Hifs and Hypoxia Markers Is Elevated In Lungs mentioning

confidence: 99%

mentioning

confidence: 99%

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Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Stockmann

Kerdiles

Nomaksteinsky

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…This is the case for Smad (similar to mothers against decapentaplegic), 49 nuclear factor (NF)-jB, 50 phosphatidyl inositol-3 kinase (PI-3K), mitogen-activated protein kinase, semaphorin 7A receptors (plexin c1 and b-integrins), 51 the focal adhesion protein Hic-5 52 and b-catenin translocation to the nucleus, and this is confirmed in lung and liver fibrosis. 53 In these 2 types, the renin-angiotensin system appears to sensitize both organs for fibrosis development, and angiotensine II receptor blockers can interrupt the autocrine TGF-b/angiotensine II loop in the myofibroblast. 54 Platelet-derived growth factor B (PDGF-B), whose hepatic overexpression was shown to induce liver fibrosis, 55 has caught clinical interest since the demonstration of stimulatory auto-antibodies to the PDGF receptor in patients suffering from systemic sclerosis (scleroderma).…”

Section: Characterization and Origin Of A Myofibroblastmentioning

confidence: 99%

Stromal myofibroblasts are drivers of invasive cancer growth

Wever¹,

Demetter²,

Mareel³

et al. 2008

Intl Journal of Cancer

631

601

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Tissue integrity is maintained by the stroma in physiology. In cancer, however, tissue invasion is driven by the stroma. Myofibroblasts and cancer-associated fibroblasts are important components of the tumor stroma. The origin of myofibroblasts remains controversial, although fibroblasts and bone marrow-derived precursors are considered to be the main progenitor cells. Myofibroblast reactions also occur in fibrosis. Therefore, we wonder whether nontumorous myofibroblasts have different characteristics and different origins as compared to tumor-associated myofibroblasts. The mutual interaction between cancer cells and myofibroblasts is dependent on multiple invasive growth-promoting factors, through direct cell-cell contacts and paracrine signals. Since fibrosis is a major side effect of radiotherapy, we address the question how the main methods of cancer management, including chemotherapy, hormonotherapy and surgery affect myofibroblasts and by inference the surrogate endpoints invasion and metastasis.

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“…In recent studies, TGF-␤ has been shown to induce rapid nuclear translocation of ␤-catenin in mesenchymal stem cells in a Smad-3-dependent manner (5). Also, a recent study showed that TGF-␤ activates the ␤-catenin pathway in lung fibroblasts through inhibition of glycogen synthase kinase-3␤ (GSK-3␤) (6). In the lung, a Gata6-Wnt/␤-catenin pathway was recently shown to be required for epithelial stem cell development and airway regeneration (7).…”

Section: Idiopathic Pulmonary Fibrosis (Ipf)mentioning

confidence: 99%

SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

Chang

Wei

Jacobs

et al. 2010

Journal of Biological Chemistry

110

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Idiopathic pulmonary fibrosis (IPF) is a poorly understood progressive disease characterized by the accumulation of scar tissue in the lung interstitium. A hallmark of the disease is areas of injury to type II alveolar epithelial cells with attendant accumulation of fibroblasts in areas called fibroblastic foci. In an effort to better characterize the lung fibroblast phenotype in IPF patients, we isolated fibroblasts from patients with IPF and looked for activation of signaling proteins, which could help explain the exaggerated fibrogenic response in IPF. We found that IPF fibroblasts constitutively expressed increased basal levels of SPARC, plasminogen activator inhibitor-1 (PAI-1), and active ␤-catenin compared with control cells. Control of basal PAI-1 expression in IPF fibroblasts was regulated by SPARCmediated activation of Akt, leading to inhibition of glycogen synthase kinase-3␤ and activation of ␤-catenin. Additionally, IPF fibroblasts (but not control fibroblasts) were resistant to plasminogen-induced apoptosis and were sensitized to plasminogen-mediated apoptosis by inhibition of SPARC or ␤-catenin. These findings uncover a newly discovered regulatory pathway in IPF fibroblasts that is characterized by elevated SPARC, giving rise to activated ␤-catenin, which regulates expression of downstream genes, such as PAI-1, and confers an apoptosisresistant phenotype. Disruption of this pathway may represent a novel therapeutic target in IPF.

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TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts

Cited by 190 publications

References 41 publications

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Stromal myofibroblasts are drivers of invasive cancer growth

SPARC Suppresses Apoptosis of Idiopathic Pulmonary Fibrosis Fibroblasts through Constitutive Activation of β-Catenin

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