Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park (RTP), NC 27709, USA.
Cell Commun Signal. 2010 Jun 10;8:10. doi: 10.1186/1478-811X-8-10.
Uterine 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.
We 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.
These 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.
子宫肌瘤（纤维瘤）是良性平滑肌肿瘤，常含有大量细胞外基质（ECM）。本研究采用共培养体系，研究了人子宫肌瘤（UtLM）细胞与子宫肌瘤衍生成纤维细胞（FB）之间的相互作用及其对细胞生长和 ECM 蛋白产生的重要性。
共培养后发现细胞增殖增强，细胞外基质胶原 I 型和胰岛素样生长因子结合蛋白-3 水平升高。UtLM 细胞与 FB 共培养的培养基中血管内皮生长因子、表皮生长因子、成纤维细胞生长因子-2、血小板衍生生长因子 A 和 B 的分泌也增加。蛋白质芯片显示上述生长因子配体的磷酸化受体酪氨酸激酶（RTKs）增加，免疫印迹显示共培养 UtLM 细胞中 RTK 下游效应物磷酸化丝裂原激活蛋白激酶 44/42 水平升高。转化生长因子-β 1 和 3 的分泌也增加，共培养 UtLM 细胞中的转化生长因子-β受体 I 免疫沉淀显示磷酸丝氨酸表达升高。共培养 UtLM 细胞中的下游效应物磷酸化小 mothers against decapentaplegic-2 和 -3 蛋白（SMAD）水平也升高。然而，与 FB 共培养的正常子宫肌细胞未见上述任何作用。肿瘤衍生成纤维细胞和/或 UtLM 细胞释放的可溶性因子以及生长因子受体及其途径的激活刺激了 UtLM 细胞的增殖，并增强了 ECM 蛋白的产生。
这些数据支持纤维瘤肿瘤细胞与 ECM 成纤维细胞之间相互作用以及生长因子和 ECM 蛋白在子宫肌瘤发病机制中的重要性。
