Complex networks of multiple factors in the pathogenesis of uterine leiomyoma

Islam, Soriful; Protic, Olga; Stortoni, Piergiorgio; Grechi, G; Lamanna, P; Petraglia, Felice; Castellucci, Mario; Ciarmela, Pasquapina

doi:10.1016/j.fertnstert.2013.03.007

Cited by 160 publications

(166 citation statements)

References 249 publications

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“…Substantial evidence exists to suggest that aberrations of certain growth factors and their receptors or signaling pathways play a significant role in growth and development of uterine fibroids (68)(69)(70)(71). These include IGF-1 (72,73), platelet-derived growth factor (PDGF) (71), vascular endothelial growth factor (VEGF) (74), EGF (75) and fibroblast growth factor (FGF) (76).…”

Section: Growth Factor Signalingmentioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

129

147

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Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

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Section: Growth Factor Signalingmentioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

129

147

View full text Add to dashboard Cite

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“…4,7,8 It is an accepted fact that leiomyomas are characterized by excessive and disordered extracellular matrix (ECM) which contributes to the total bulk of the tumor. 9,10 Furthermore, the tumor is characterized by increased stiffness as studied in vitro 11,12 or in vivo by magnetic resonance elastography. 13,14 Cells sense the changes in the surrounding stiffness as mechanical cues and translate them into biochemical signals.…”

Section: Introductionmentioning

confidence: 99%

Leiomyoma Cells in 3-Dimensional Cultures Demonstrate an Attenuated Response to Fasudil, a Rho-Kinase Inhibitor, When Compared to 2-Dimensional Cultures

et al. 2014

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Uterine leiomyomata are common benign tumors in women of reproductive age and demonstrate an attenuated response to mechanical signaling that involves Rho and integrins. To further characterize the impairment in Rho signaling, we studied the effect of Rho-kinase inhibitor, fasudil, on extracellular matrix production, in 2-dimensional (2D) and 3-dimensional (3D) cultures of leiomyoma and myometrial cells. Leiomyoma 2D cultures demonstrated a rapid decrease in gene transcripts and protein for fibronectin, procollagen 1A, and versican. In 3D cultures, fibronectin and procollagen 1A proteins demonstrated increased levels at lower concentrations of fasudil, followed by a concentration-dependent decrease. Versican protein increased up to 3-fold, whereas fibromodulin demonstrated a significant decrease of 1.92-fold. Myometrial 2D or 3D cultures demonstrated a decrease in all proteins after 72 hours of treatment. The 3D leiomyoma cultures demonstrated a significant increase in active RhoA, followed by a concentration-dependent decrease at higher concentrations. A concentration-dependent increase in phosphoextracellular regulated signal kinase and proapoptotic protein Bax was observed in 3D leiomyoma cultures. Fasudil relaxed the contraction of the 3D collagen gels caused by myometrium and leiomyoma cell growth. These findings indicate that the altered state of Rho signaling in leiomyoma was more clearly observed in 3D cultures. The results also suggest that fasudil may have clinical applicability for treatment of uterine leiomyoma.

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“…Uterine fibroids are characterized by smooth muscle proliferation and excessive extracellular matrix deposition. Although several complex cellular and molecular signaling network abnormalities have been described as initiators and promoters in the development and growth of leiomyomas (23), their exact etiology is not well understood. In fact, multiple genetic, familial, sex steroid, and growth factor abnormalities have been associated with the development of uterine leiomyomas (24 -26).…”

mentioning

confidence: 99%

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells

Borahay

Kılıç

Yallampalli

et al. 2014

Journal of Biological Chemistry

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Background: Statins have broad-reaching effects beyond lowering plasma lipids, including antitumor properties. Results: Simvastatin inhibits proliferation and induces calcium-dependent apoptosis of human uterine leiomyoma cells. Conclusion:We report a novel calcium-mediated pathway associated with antitumor properties of simvastatin. Significance: Simvastatin may have antitumor properties significant for the treatment of human uterine leiomyomas.

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Complex networks of multiple factors in the pathogenesis of uterine leiomyoma

Cited by 160 publications

References 249 publications

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Leiomyoma Cells in 3-Dimensional Cultures Demonstrate an Attenuated Response to Fasudil, a Rho-Kinase Inhibitor, When Compared to 2-Dimensional Cultures

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells

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