Abstract
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.
Highlights
Uterine leiomyomas are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM)
The leiomyoma-derived fibroblasts (Figure 1D) were negative for the oxytocin receptor (OTR), indicating that the FB were not uterine smooth muscle cells. Both the uterine leiomyoma (UtLM) cells (Figure 1E) and uterine smooth muscle (myometrial) cells (UtSMC) (Figure 1F) were positive for the OTR, a G protein coupled receptor expressed in the myometrium [11] and leiomyomas [12,13]
We found that many of the growth factors associated with proliferation and fibrogenesis, such as epidermal growth factor (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
Summary
Uterine leiomyomas (fibroids) are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM). 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. There are few studies that have investigated the significance of the "inherent" unique composition of these tumors in the pathogenesis of uterine leiomyomas. These firm, circumscribed masses are known to possess a smooth muscle component, and may often have a significant extracellular matrix (ECM). It has been suggested that, in general, the growth of tumors is dependent on interactions between multiple inter-dependent cell types [8]
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