TGF-β Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

Kahata, Kaoru; Dadras, Mahsa Shahidi; Moustakas, Aristidis

doi:10.1101/cshperspect.a022194

Cited by 102 publications

(95 citation statements)

References 238 publications

(345 reference statements)

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“…TGF-β signals through cell surface type I transmembrane receptors, which heterodimerize with the type II receptors, leading to activation of canonical Smad2/3/4 pathways and Smad independent pathways including: Rho, p38MAPK and PI3 kinase. These signaling pathways regulate the actin cytoskeleton and gene expression of cell cycle regulators, cytokines matrix proteins and proteases [16, 17]. The role of TGF-β signaling in breast fibroblasts during breast cancer progression is complex.…”

Section: Introductionmentioning

confidence: 99%

CXCL1 Derived from Mammary Fibroblasts Promotes Progression of Mammary Lesions to Invasive Carcinoma through CXCR2 Dependent Mechanisms

Bernard

Myers

Fang

et al. 2018

J Mammary Gland Biol Neoplasia

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With improved screening methods, the numbers of abnormal breast lesions diagnosed in women have been increasing over time. However, it remains unclear whether these breast lesions will develop into invasive cancers. To more effectively predict the outcome of breast lesions and determine a more appropriate course of treatment, it is important to understand the underlying mechanisms that regulate progression of non-invasive lesions to invasive breast cancers. A hallmark of invasive breast cancers is the accumulation of fibroblasts. Fibroblast proliferation and activation in the mammary gland is in part regulated by the Transforming Growth Factor beta1 pathway (TGF-β). In animal models, TGF-β suppression of CCL2 and CXCL1 chemokine expression is associated with metastatic progression of mammary carcinomas. Here, we show that transgenic overexpression of the Polyoma middle T viral antigen in the mouse mammary gland of C57BL/6 mice results in slow growing non-invasive lesions that progress to invasive carcinomas in a stage dependent manner. Invasive carcinomas are associated with accumulation of fibroblasts that show decreased TGF-β expression and high levels of CXCL1, but not CCL2. Using co-transplant models, we show that decreased TGF-β signaling in fibroblasts contribute to mammary carcinoma progression through enhancement of CXCL1/CXCR2 dependent mechanisms. Using cell culture models, we show that CXCL1 mediated mammary carcinoma cell invasion through NF-κB, AKT, Stat3 and p42/44MAPK dependent mechanisms. These studies provide novel mechanistic insight into the progression of pre-invasive lesions and identify new stromal biomarkers, with important prognostic implications.

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Section: Introductionmentioning

confidence: 99%

CXCL1 Derived from Mammary Fibroblasts Promotes Progression of Mammary Lesions to Invasive Carcinoma through CXCR2 Dependent Mechanisms

Bernard

Myers

Fang

et al. 2018

J Mammary Gland Biol Neoplasia

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“…The process of nerve navigation during tooth development is strictly regulated by signalling networks, such as semaphorin 3A, 40 TGF‐β 41 and activin signalling, 42 and closely associated with tooth morphogenesis. Recent studies illuminate that in mice incisor, sensory nerve fibres secrete sonic hedgehog protein to activate Gli1 + cells, which is a critical subpopulation of MSCs differentiating into odontoblasts and pulp cells 5 .…”

Section: Discussionmentioning

confidence: 99%

Sensory nerve‐deficient microenvironment impairs tooth homeostasis by inducing apoptosis of dental pulp stem cells

et al. 2020

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Objectives:The aim of this study is to investigate the role of sensory nerve in tooth homeostasis and its effect on mesenchymal stromal/stem cells (MSCs) in dental pulp. Materials and methods:We established the rat denervated incisor models to identify the morphological and histological changes of tooth. The groups were as follows:IANx (inferior alveolar nerve section), SCGx (superior cervical ganglion removal), IANx + SCGx and Sham group. The biological behaviour of dental pulp stromal/ stem cells (DPSCs) was evaluated. Finally, we applied activin B to DPSCs from sensory nerve-deficient microenvironment to analyse the changes of proliferation and apoptosis. Results: Incisor of IANx and IANx + SCGx groups exhibited obvious disorganized tooth structure, while SCGx group only showed slight decrease of dentin thickness, implying sensory nerve, not sympathetic nerve, contributes to the tooth homeostasis. Moreover, we found sensory nerve injury led to disfunction of DPSCs via activin B/SMAD2/3 signalling in vitro. Supplementing activin B promoted proliferation and reduced apoptosis of DPSCs in sensory nerve-deficient microenvironment. Conclusions: This research first demonstrates that sensory nerve-deficient microenvironment impairs tooth haemostasis by inducing apoptosis of DPSCs via activin B/ SMAD2/3 signalling. Our study provides the evidence for the crucial role of sensory nerve in tooth homeostasis.

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“…We speculate that this outcome may be a result of EMT being affected in ESCC. EMT is an important process in cancer metastasis, with 90% of tumors exhibiting different degrees of EMT during tumor development . During this process, the epithelial cells attenuate the expression of epithelial characteristics and gain mesenchymal phenotype properties .…”

Section: Discussionmentioning

confidence: 99%

“…EMT is an important process in cancer metastasis, with 90% of tumors exhibiting different degrees of EMT during tumor development. [33][34][35] During this process, the epithelial cells attenuate the expression of epithelial characteristics and gain mesenchymal phenotype properties. 36,37 In this study, we surprisingly found that blocking FGFR4 suppressed EMT in ESCC cells, including the upregulation of epithelial markers (E- cadherin and Claudin-1) and the downregulation of mesenchymal markers (N-cadherin, Vimentin, and Snail).…”

Section: Discussionmentioning

confidence: 99%

Blocking FGFR4 exerts distinct anti‐tumorigenic effects in esophageal squamous cell carcinoma

et al. 2018

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BackgroundThe FGFR family can be activated by FGFs and plays important roles in regulating cell growth, differentiation, migration, and angiogenesis. Recent studies have suggested that FGFR4 could regulate several processes, including tumor progression. Esophageal squamous cell carcinoma (ESCC) is a malignancy with high global occurrence. However, the molecule mechanism and the potential roles of FGFR4 in ESCC remain unknown.MethodsImmunohistochemistry and Western blotting were used to detect FGFR4 expression in ESCC samples and cell lines. Cell counting kit‐8, and clonogenic, transwell, flow cytometric, and tumor xenograft in nude mice assays were utilized to determine the effect of blocking FGFR4 in proliferation, invasion, migration, and apoptosis of ESCC cells.ResultsFGFR4 is frequently overexpressed in ESCC tissue and cell lines. in vitro assays have shown that blocking FGFR4 by a specific blocker, H3B‐6527, significantly decreases proliferation, invasion, and migration, and alters epithelial‐mesenchymal transition markers in ESCC cells. In addition, FGFR4 blockade is associated with the induction of apoptosis and affects PI3K/Akt and MAPK/ERK pathways. Moreover, FGFR4 blockade could significantly inhibit the growth of xenograft tumors in vivo.ConclusionOur findings suggest that blocking FGFR4 significantly suppresses the malignant behaviors of ESCC and indicate that FGFR4 is a potential target for the treatment of ESCC.

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TGF-β Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

Cited by 102 publications

References 238 publications

CXCL1 Derived from Mammary Fibroblasts Promotes Progression of Mammary Lesions to Invasive Carcinoma through CXCR2 Dependent Mechanisms

CXCL1 Derived from Mammary Fibroblasts Promotes Progression of Mammary Lesions to Invasive Carcinoma through CXCR2 Dependent Mechanisms

Sensory nerve‐deficient microenvironment impairs tooth homeostasis by inducing apoptosis of dental pulp stem cells

Blocking FGFR4 exerts distinct anti‐tumorigenic effects in esophageal squamous cell carcinoma

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