Nuclear <scp>GSK</scp>‐3β segregation in desmoid‐type fibromatosis

Meneghello, Cristiana; Ousghir, Bouchra; Rastrelli, Marco; Anesi, Laura; Sommariva, Antonio; Montesco, Maria Cristina; Róssi, Carlo; Hladnik, Uroš; Segat, Daniela

doi:10.1111/his.12133

Cited by 8 publications

(9 citation statements)

References 34 publications

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“…Meneghello et al. reported results inconsistent with those of our study, namely that mRNA expression of cyclin D was decreased in all desmoid cells harboring different mutation status compared with control cells, whereas that of Axin2 increased . This discrepancy between our studies might be due to differences in the control cells used.…”

Section: Discussioncontrasting

confidence: 99%

“…Effectiveness of drugs had better be analyzed by not only cell viability test, but also gene expression patterns of target genes because downstream of Tcf/Lef transcription pathway should have crucial roles in tumorigenesis of desmoid tumors. Meneghello et al reported results inconsistent with those of our study, namely that mRNA expression of cyclin D was decreased in all desmoid cells harboring different mutation status compared with control cells, whereas that of Axin2 increased [28]. This discrepancy between our studies might be due to differences in the control cells used.…”

Section: Discussioncontrasting

confidence: 99%

“…Nuclear accumulation of β ‐catenin is considered to activate T‐cell factor, which in turn stimulates Tcf/Lef transcriptional gene expression . The expression of these genes including Axin2, c‐Myc, Cyclin D1 has been shown to be increased in desmoid tumor . In this study, expression patterns of these target genes altered among cells harboring different mutation types.…”

Section: Discussionmentioning

confidence: 73%

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Characteristics of cultured desmoid cells with different CTNNB1 mutation status

et al. 2015

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Desmoid tumors are benign mesenchymal neoplasms with a locally aggressive nature. The mutational status of β‐catenin gene (CTNNB1) is presumed to affect the tumorous activity of the cells. In this study, we isolated three kinds of desmoid cell with different CTNNB1 status, and compared their characteristics. Cells were isolated from three patients with abdominal wall desmoid during surgery, all of which were resistant to meloxicam treatment. The mutational status of the CTNNB1 exon 3 was determined for both parental tumor tissues and isolated cultured cells. β‐catenin expression was determined with immunohistochemistry. Responsiveness to meloxicam was investigated with MTS assay together with COX‐2 immunostaining. mRNA expressions of downstream molecules of Wnt/β‐catenin pathway were determined with real‐time RT‐PCR. Three kinds of cell isolated from desmoid tumors harboring different CTNNB1 mutation status (wild type, T41A, and S45F), all exhibited a spindle shape. These isolated cells could be cultured until the 20th passage with unchanged proliferative activity. Nuclear accumulation of β‐catenin was observed in all cultured cells, particularly in those with S45F. Proliferating activity was significantly suppressed by meloxicam (25 μmol/L, P < 0.007) in all three cell cultures, of which parental desmoid was resistant to meloxicam clinically. The mRNA expressions of Axin2, c‐Myc, and Cyclin D1 differently increased in the three cultured cell types as compared with those in human skin fibroblast cells (HDF). Inhibitors of Wnt/β‐catenin pathway downregulated Axin2, c‐Myc, and Cyclin D1 significantly. Isolated and cultured desmoid tumor cells harboring any one of the CTNNB1 mutation status had unique characteristics, and could be useful to investigate desmoid tumors with different mutation status of CTNNB1.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 73%

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Characteristics of cultured desmoid cells with different CTNNB1 mutation status

et al. 2015

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“…These codons are the serine and threonine phosphorylation sites required for β-catenin degradation [ 116 , 117 ]. Therefore, these mutations make phosphorylation impossible and promote β-catenin nuclear translocation [ 118 ]. A high level of nuclear β-catenin staining is the conventional diagnostic marker for DFs.…”

Section: Desmoid-type Fibromatosis: a Pathology Arising From Wnt Pathmentioning

confidence: 99%

The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target

Enzo¹,

Rastrelli

Róssi

et al. 2015

Molecular and Cellular Therapies

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The canonical Wnt signaling pathway is involved in a variety of biological processes like cell proliferation, cell polarity, and cell fate determination. This pathway has been extensively investigated as its deregulation is linked to different diseases, including various types of cancer, skeletal defects, birth defect disorders (including neural tube defects), metabolic diseases, neurodegenerative disorders and several fibrotic diseases like desmoid tumors. In the "on state", beta-catenin, the key effector of Wnt signaling, enters the nucleus where it binds to the members of the TCF-LEF family of transcription factors and exerts its effect on gene transcription. Disease development can be caused by direct or indirect alterations of the Wnt/β-catenin signaling.In the first case germline or somatic mutations of the Wnt components are associated to several diseases such as the familial adenomatous polyposis (FAP) - caused by germline mutations of the tumor suppressor adenomatous polyposis coli gene (APC) - and the desmoid-like fibromatosis, a sporadic tumor associated with somatic mutations of the β-catenin gene (CTNNB1).In the second case, epigenetic modifications and microenvironmental factors have been demonstrated to play a key role in Wnt pathway activation. The natural autocrine Wnt signaling acts through agonists and antagonists competing for the Wnt receptors. Anomalies in this regulation, whichever is their etiology, are an important part in the pathogenesis of Wnt pathway linked diseases. An example is promoter hypermethylation of Wnt antagonists, such as SFRPs, that causes gene silencing preventing their function and consequently leading to the activation of the Wnt pathway. Microenvironmental factors, such as the extracellular matrix, growth factors and inflammatory mediators, represent another type of indirect mechanism that influence Wnt pathway activation. A favorable microenvironment can lead to aberrant fibroblasts activation and accumulation of ECM proteins with subsequent tissue fibrosis that can evolve in fibrotic disease or tumor.Since the development and progression of several diseases is the outcome of the Wnt pathway cross-talk with other signaling pathways and inflammatory factors, it is important to consider not only direct inhibitors of the Wnt signaling pathway but also inhibitors of microenvironmental factors as promising therapeutic approaches for several tumors of fibrotic origin.

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“…Although the morphologies of these tumors have been well characterized, their nature and pathogenesis have remained obscure for many years [6, 9]. According to the literature, the median age at the diagnosis of DFs is about 35 years, and the majority of patients are women [10].…”

Section: Discussionmentioning

confidence: 99%

Desmoid Fibromatosis of the Abdominal Wall: Surgical Resection and Reconstruction with Biological Matrix Egis®

Tropea¹,

Mocellin²,

Stramare³

et al. 2017

Case Rep Oncol

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Desmoid tumor is a rare monoclonal fibroblast proliferation that is regarded as benign. The clinical management of desmoid tumors is very complex and requires a multidisciplinary approach because of the unpredictable disease course. For those cases localized in the anterior abdominal wall, symptomatic and unresponsive to medical treatment, radical resection and reconstruction with a prosthetic device are indicated. We present here a case of desmoid fibromatosis of the left anterolateral abdominal wall with a marked increase of the mass that required a large excision followed by reconstruction with biological matrix. The fact that it can be incorporated in patient tissue without a fibrotic response and that it can resist future infections, together with a very competetive price, made the new collagen matrix Egis^® our first choice.

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Nuclear GSK‐3β segregation in desmoid‐type fibromatosis

Abstract: Our data suggest that GSK-3β is an additional DF marker with an important role in the aetiopathogenesis of this entity.

Cited by 8 publications

References 34 publications

Characteristics of cultured desmoid cells with different CTNNB1 mutation status

Characteristics of cultured desmoid cells with different CTNNB1 mutation status

The Wnt/β-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target

Desmoid Fibromatosis of the Abdominal Wall: Surgical Resection and Reconstruction with Biological Matrix Egis®

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