Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata

Sozen, Ibrahim; Arıcı, Aydın

doi:10.1016/s0015-0282(02)03154-0

Cited by 155 publications

(136 citation statements)

References 107 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

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“…По мнению ряда авторов, у пациенток с суб-мукозной и интрамуральной формами лейо-миом состояние миометрия и эндометрия вне зависимости от деформации полости матки характеризуется хроническим воспалительным процессом и, как следствие, неудовлетворитель-ными показателями фертильности [11,19,20].…”

Section: Discussionunclassified

Pathogenetic determinants of endometrial dysfunction in patients with myoma

Tolibova

Хайбуллоевна

2018

Z.akus.zen.bolezn

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Introduction. Among the patients with infertility associated with small forms of uterine fibroids (subserous and intra mural), there are a high incidence of inflammatory changes in the cervix, chronic salpingo-opharitis, hydrosalpinx, adhesive process in pelvic organs, chronic endocervicitis and endometrial dysfunction were identified more frequently. The aim of the study was to investigate the clinical and morphological features of endometrial dysfunction in patients with infertility associated with uterine myoma. Material and methods. The study included 165 patients: 70 patients with primary infertility, 65 women with secondary infertility and 30 patients in the control group. All patients were examined and treated in The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott. Laparoscopic and hysteroscopic examination followed by endometrial biopsy was performed on the 19-24th day of the menstrual cycle. Immunohistochemical method was used to study the expression of ER, PR receptors, proinflammatory markers (CD8+, CD20+, CD4+, CD138+), endothelial marker (CD34+) and p16ink4a oncoprotein expression. Estimation of ER and PR expression was carried out by semi-quantitative method of H-Score, other markers, by computer image analysis system “Morphology 5.0” (VideoTest, Russia). Statistical processing of the results was performed using statistical packages (Stata 13). Results. In group of patients with infertility associated with small forms of subserous and intramural uterine myomas, pathognomonic signs of endometrial dysfunction were: high frequency of chronic endometritis, pathological activation of neoangiogenesis, positive expression of inhibitor of cyclin-dependent kinase p16ink4a, reduction of ER and PR expression in the stromal endometrial component, change in receptor affinity of sex steroid hormones.

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“…These include TGF-h, insulin-like growth factors 1 and 2, basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor (65). TGF-h has been of particular interest, and previous studies on human leiomyomas have found that these tumors express TGF-h receptors and SMADs and overexpress TGF-h1 and TGF-h3 compared with normal myometrium (66,67).…”

Section: Discussionmentioning

confidence: 99%

Tumor-Specific Efficacy of Transforming Growth Factor-βRI Inhibition in Eker Rats

Laping

Everitt

Frazier

et al. 2007

Clinical Cancer Research

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Purpose: Transforming growth factor β (TGF-β), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-β signaling could be efficacious for lesions in which TGF-β promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions. Experimental Design: We examined the effect of a TGF-β inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency. Results: Blockade of TGF-β signaling with the ALK5/type I TGF-βR kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals. Conclusion: Although pharmacologic inhibition of TGF-β signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.

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Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata

Cited by 155 publications

References 107 publications

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Pathogenetic determinants of endometrial dysfunction in patients with myoma

Tumor-Specific Efficacy of Transforming Growth Factor-βRI Inhibition in Eker Rats

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