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Wolańska, Małgorzata; Sobolewski, Krzysztof; Drozdzewicz, M; Bańkowski, Edward

doi:10.1023/a:1006914301565

Cited by 50 publications

(15 citation statements)

References 21 publications

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“…The most common symptom is abnormal bleeding which may require surgical removal of the uterus due to symptom severity (Walker and Stewart, 2005; Sabry and Al-Hendy, 2012). The tumors are composed of excessive extracellular fibrous proteins including the collagens, proteoglycans and glycosamines (Wolańska et al, 1998; Nowak, 2001; Malik et al, 2010). It is the excessive amount of extracellular matrix (ECM) secreted by the leiomyoma cells that makes up the tumor bulk resulting in symptoms (Fujita, 1985; Wolańska et al, 1998; Mitropoulou et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…The tumors are composed of excessive extracellular fibrous proteins including the collagens, proteoglycans and glycosamines (Wolańska et al, 1998; Nowak, 2001; Malik et al, 2010). It is the excessive amount of extracellular matrix (ECM) secreted by the leiomyoma cells that makes up the tumor bulk resulting in symptoms (Fujita, 1985; Wolańska et al, 1998; Mitropoulou et al, 2001). Proteins of the matrix bind to transmembrane cell surface adhesion receptors, called integrins, that connect the ECM to the intracellular actin cytoskeleton and via signaling molecules initiate intracellular cascades which control cell shape, migration, proliferation, differentiation and survival (Giancotti and Ruoslahti, 1999; Belkin and Stepp, 2000; Miranti and Brugge, 2002; Schwartz and Ginsberg, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Integrin β1 regulates leiomyoma cytoskeletal integrity and growth

2012

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Uterine leiomyomas are characterized by an excessive extracellular matrix, increased mechanical stress, and increased active RhoA. Previously, we observed that mechanical signaling was attenuated in leiomyoma, but the mechanisms responsible remain unclear. Integrins, especially integrin β1, are transmembrane adhesion receptors that couple extracellular matrix stresses to the intracellular cytoskeleton to influence cell proliferation and differentiation. Here we characterized integrin and laminin to signaling in leiomyoma cells. We observed a 2.25 ± 0.32 fold increased expression of integrin β1 in leiomyoma cells, compared to myometrial cells. Antibody-mediated inhibition of integrin β1 led to significant growth inhibition in leiomyoma cells and a loss of cytoskeletal integrity. Specifically, polymerization of actin filaments and formation of focal adhesions were reduced by inhibition of integrin p1. Inhibition of integrin β1 in leiomyoma cells led to 0.81 ± 0.02 fold decrease in active RhoA, and resembled levels found in serum-starved cells. Likewise, inhibition of integrin β1 was accompanied by a decrease in phospho-ERK. Compared to myometrial cells, leiomyoma cells demonstrated increased expression of integrin α6 subunit to laminin receptor (1.91 ± 0.11 fold), and increased expression of laminin 5α (1.52±0.02), laminin 5β (3.06±0.92), and laminin 5γ (1.66 ± 0.06). Of note, leiomyoma cells grown on laminin matrix appear to realign themselves. Taken together, the findings reveal that the attenuated mechanical signaling in leiomyoma cells is accompanied by an increased expression and a dependence on integrin β1 signaling in leiomyoma cells, compared to myometrial cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrin β1 regulates leiomyoma cytoskeletal integrity and growth

2012

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“…Prolidase activity is related to the pathogenesis of various diseases Savas et al 2010;Sezen et al 2010;Toy et al 2009aToy et al , 2010Vural et al 2010b;Yildiz et al 2008a). Since its property of representation of collagen turnover, prolidase is an important marker for tumour size and aggression of the fi broid growth (Wolanska et al 2001). …”

Section: Introductionmentioning

confidence: 99%

Oxidative stress and prolidase activity in women with uterine fibroids

Vural

Camuzcuoğlu

Toy

et al. 2011

Journal of Obstetrics and Gynaecology

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The aim of this study was to investigate oxidative stress markers and prolidase activity in serum and tissue samples of women with uterine fibroids, with further analysis on position and size. Lipid hydroperoxide, ceruloplasmin, catalase, arylesterase, free sulfhydryl group activity and prolidase activity levels were measured in fibroid tissue, myometrial tissue and serum of the same patients (n = 51), at the same time. Results show that ceruloplasmin, catalase, arylesterase, free sulfhydryl group and prolidase activities were higher in fibroid tissue than those in myometrial tissue (p = 0.003, 0.009, 0.004, 0.02, 0.008, respectively). Serum levels of catalase and prolidase were lower, and arylesterase and free sulfhydryl groups were higher in the fibroid group than those in the control group (p < 0.001 for all). Fibroid volume in submucosal subgroup of the fibroid group yield significant correlation with ceruloplasmin, catalase, arylesterase and prolidase activities (r = 0.84, p = 0.02; r = 0.93, p < 0.001; r = 0.63, p = 0.049 and r = 0.87, p = 0.01, respectively). Despite the lack of statistical significance, the highest levels of prolidase activity were found in fibroid samples, especially in submucosal ones. It is concluded that this study demonstrated increased antioxidative repair system in the fibroid tissue compared to the myometrium and serum of the same patients. Additionally, higher pathophysiological potential of the submucosal fibroids over intramural and subserosal fibroids were shown with the levels of oxidative stress markers and prolidase activity levels.

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“…It is believed that indeed, the pathogenesis of leiomyomas at the cellular and molecular levels involves the interactions of cytokines/growth factors, as well as ECM components, that all play a pivotal role in the development of these tumors [26]. Furthermore, it has been suggested that some of the sulphated glycosaminoglycans (GAGs), such as heparan sulfate and heparin in the ECM, are involved in creating a storage depot for biologically active molecules, such as growth factors and enzymes, and under conditions of hydrolytic degradation of the GAGs there may be a release of cytokines and other factors that may promote tumor cell growth and stimulate collagen biosynthesis [27]. In this study, we found that many of the growth factors associated with proliferation and fibrogenesis, such as EGF, TGF-β1, TGF-β3, VEGF, FGF-2, and PDGF-A and -B were increased in the media of cocultured UtLM cells, which suggested that these soluble factors are capable of stimulating the proliferation of UtLM cells and collagen I production.…”

Section: Discussionmentioning

confidence: 99%

Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture

Moore

Swartz

et al. 2010

Cell Commun Signal

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BackgroundUterine leiomyomas (fibroids) are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM). In the present study, we investigated the interactions between human uterine leiomyoma (UtLM) cells and uterine leiomyoma-derived fibroblasts (FB), and their importance in cell growth and ECM protein production using a coculture system.ResultsWe found enhanced cell proliferation, and elevated levels of ECM collagen type I and insulin-like growth factor-binding protein-3 after coculturing. There was also increased secretion of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor-2, and platelet derived growth factor A and B in the media of UtLM cells cocultured with FB. Protein arrays revealed increased phosphorylated receptor tyrosine kinases (RTKs) of the above growth factor ligands, and immunoblots showed elevated levels of the RTK downstream effector, phospho-mitogen activated protein kinase 44/42 in cocultured UtLM cells. There was also increased secretion of transforming growth factor-beta 1 and 3, and immunoprecipitated transforming growth factor-beta receptor I from cocultured UtLM cells showed elevated phosphoserine expression. The downstream effectors phospho-small mothers against decapentaplegic -2 and -3 protein (SMAD) levels were also increased in cocultured UtLM cells. However, none of the above effects were seen in normal myometrial cells cocultured with FB. The soluble factors released by tumor-derived fibroblasts and/or UtLM cells, and activation of the growth factor receptors and their pathways stimulated the proliferation of UtLM cells and enhanced the production of ECM proteins.ConclusionsThese data support the importance of interactions between fibroid tumor cells and ECM fibroblasts in vivo, and the role of growth factors, and ECM proteins in the pathogenesis of uterine fibroids.

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Untitled

Cited by 50 publications

References 21 publications

Integrin β1 regulates leiomyoma cytoskeletal integrity and growth

Integrin β1 regulates leiomyoma cytoskeletal integrity and growth

Oxidative stress and prolidase activity in women with uterine fibroids

Human uterine leiomyoma-derived fibroblasts stimulate uterine leiomyoma cell proliferation and collagen type I production, and activate RTKs and TGF beta receptor signaling in coculture

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