Fibroblast growth factors (FGF) in human myometrium and uterine leiomyomas in various stages of tumour growth

Wolańska, Małgorzata; Bańkowski, Edward

doi:10.1016/j.biochi.2005.07.014

Cited by 30 publications

(37 citation statements)

References 19 publications

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“…The enhanced growth of leiomyomas may be due partially to the presence of large quantities of bFGF stored in the extracellular matrix (ECM) of these tumors (24). The expression of FGF receptor protein was also reported to be more intense in leiomyomas than in the myometrium (25). Another potent mitogen for smooth muscle cells is PDGF, its mRNA is expressed in both leiomyomas and in myometrium, and its receptor sites per cell are seen more in leiomyomas than in the myometrium (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…It exerts its mitogenic action by increasing DNA synthesis, accelerating the progression of the cell cycle from G-to S-phase, and inhibiting apoptosis (6). Several studies have indicated increased expression of IGF-I mRNA and higher tissue concentrations of IGF-I protein in leiomyomas versus corresponding myometrium (37)(38)(39). Our previous study also found that IGF-I peptide immunolocalized to the leiomyoma cells and the fibroblasts in the bands of intervening connective tissue comprising the extracellular matrix in some leiomyomas; the latter was not seen in the myometrial samples.…”

Section: Discussionmentioning

confidence: 99%

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Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Saile

Swartz

et al. 2008

Mol Med

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Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02-0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR observed in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings; and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that leiomyomas overexpressed IGF-IRβ and phosphorylated IGF-IRβ. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P < 0.02-0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P < 0.0001), and that phosphorylated IGF-IRβ, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P < 0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IRβ blocked these effects. These data indicate that overexpression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Saile

Swartz

et al. 2008

Mol Med

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“…34,35 It has been postulated that both FGF1 and FGF2 play important roles in transformation of normal myometrium into leiomyoma and further growth of this tumor. 36 Expression of PDGFA and PDGFB is higher in leiomyoma tissue than in matched myometrial tissue and the expression of PDGF and its receptors in leiomyoma and myometrial tissue varied during the menstrual cycle. 37 The same authors speculated that PDGF may play a role in the pathogenesis of leiomyomas through mechanisms that include proliferation and increased expression of extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

Fibroid-Associated Heavy Menstrual Bleeding: Correlation Between Clinical Features, Doppler Ultrasound Assessment of Vasculature, and Tissue Gene Expression Profiles

et al. 2013

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Despite the prevalence of uterine fibroids (Fs), few studies have investigated the links between clinical features and the cellular or molecular mechanisms that drive F growth and development. Such knowledge will ultimately help to differentiate symptomatic from asymptomatic Fs and could result in the development of more effective and individualized treatments. The aim of this study was to investigate the relationship between ultrasound appearance, blood flow, and angiogenic gene expression in F, perifibroid (PM), and distant myometrial (DM) tissues. We hypothesized that angiogenic gene expression would be increased in tissues and participants that showed increased blood flow by Doppler ultrasound. The study was performed using Doppler ultrasound to measure blood flow prior to hysterectomy, with subsequent tissue samples from the F, PM, and DM being investigated for angiogenic gene expression. Overall, PM blood flow (measured as peak systolic velocity [PSV]) was higher than F blood flow, although significant heterogeneity was seen in vascularity and blood flow between different Fs and their surrounding myometrium. We did not find any correlation between PSV and any other clinical or molecular parameter in this study. We identified 19 angiogenesis pathway-related genes with significant differences in expression between F and DM, and 2 genes, matrix metalloproteinase 9 (MMP9) and Neuropilin 2 (NRP2), that were significantly different between F and PM. These results are consistent with subtle differences between PM and DM. Understanding the differences between symptomatic versus asymptomatic Fs may eventually lead to more effective treatments that directly target the source of heavy menstrual bleeding.

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“…To measure IGF-I concentration in testicular extracts, testes were weighed, homogenated in 500 AL of 0.05 mol/L Tris/HCl (pH 7.6) plus protease inhibitors, and then submitted to ultrasonication followed by centrifugation, as previously published (26). IGF-I content in testicular extracts and in medium recovered from each well of R2C and TM3 cells was determined following extraction and assay protocols provided with the mouse/rat IGF-I RIA kit (DSL 2900; Diagnostic System Laboratories).…”

Section: Methodsmentioning

confidence: 99%

Insulin-Like Growth Factor-I, Regulating Aromatase Expression through Steroidogenic Factor 1, Supports Estrogen-Dependent Tumor Leydig Cell Proliferation

Sirianni¹,

Chimento²,

Malivindi³

et al. 2007

Cancer Research

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The aim of this study was to investigate the role of estrogens in Leydig cell tumor proliferation. We used R2C rat Leydig tumor cells and testicular samples from Fischer rats with a developed Leydig tumor. Both experimental models express high levels of aromatase and estrogen receptor A (ERA). Treatment with exogenous 17B-estradiol (E 2 ) induced proliferation of R2C cells and up-regulation of cell cycle regulators cyclin D1 and cyclin E, the expression of which was blocked by addition of antiestrogens. These observations led us to hypothesize an E 2 /ERA-dependent mechanism for Leydig cell tumor proliferation. In determining the molecular mechanism responsible for aromatase overexpression, we found that total and phosphorylated levels of transcription factors cyclic AMP-responsive element binding protein and steroidogenic factor 1 (SF-1) were higher in tumor samples. Moreover, we found that tumor Leydig cells produce high levels of insulin-like growth factor I (IGF-I), which increased aromatase mRNA, protein, and activity as a consequence of increased total and phosphorylated SF-1 levels. Specific inhibitors of IGF-I receptor, protein kinase C, and phosphatidylinositol 3-kinase determined a reduction in SF-1 expression and in IGF-I-dependent SF-1 recruitment to the aromatase PII promoter. The same inhibitors also inhibited aromatase expression and activity and, consequently, R2C cell proliferation. We can conclude that one of the molecular mechanisms determining Leydig cell tumorigenesis is an excessive estrogen production that stimulates a short autocrine loop determining cell proliferation. In addition, cell-produced IGF-I amplifies estrogen signaling through an SF-1-dependent up-regulation of aromatase expression. The identification of this molecular mechanism will be helpful in defining new therapeutic approaches for Leydig cell tumors. [Cancer Res 2007;67(17):8368-77]

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Fibroblast growth factors (FGF) in human myometrium and uterine leiomyomas in various stages of tumour growth

Cited by 30 publications

References 19 publications

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Fibroid-Associated Heavy Menstrual Bleeding: Correlation Between Clinical Features, Doppler Ultrasound Assessment of Vasculature, and Tissue Gene Expression Profiles

Insulin-Like Growth Factor-I, Regulating Aromatase Expression through Steroidogenic Factor 1, Supports Estrogen-Dependent Tumor Leydig Cell Proliferation

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