Department of Experimental and Clinical Medicine, Faculty of Medicine, Università Politecnica delle Marche, via Tronto 10/a, Ancona 60020, Italy.
Biotechnology and Microbiology Laboratory, Department of Botany, University of Rajshahi, Rajshahi 6205, Bangladesh.
Hum Reprod Update. 2018 Jan 1;24(1):59-85. doi: 10.1093/humupd/dmx032.
Uterine leiomyoma (also known as fibroid or myoma) is the most common benign tumor of the uterus found in women of reproductive age. It is not usually fatal but can produce serious clinical symptoms, including excessive uterine bleeding, pelvic pain or pressure, infertility and pregnancy complications. Due to lack of effective medical treatments surgery has been a definitive choice for the management of this tumor.
Extracellular matrix (ECM) accumulation and remodeling are thought to be crucial for fibrotic diseases such as uterine leiomyoma. Indeed, ECM plays important role in forming the bulk structure of leiomyoma, and the ECM-rich rigid structure within these tumors is thought to be a cause of abnormal bleeding and pelvic pain. Therefore, a better understanding of ECM accumulation and remodeling is critical for developing new therapeutics for uterine leiomyoma.
PubMed and Google Scholar were searched for all original and review articles/book chapters related to ECM and medical treatments of uterine leiomyoma published in English until May 2017.
This review discusses the involvement of ECM in leiomyoma pathogenesis as well as current and future medical treatments that target ECM directly or indirectly. Uterine leiomyoma is characterized by elevated levels of collagens, fibronectin, laminins and proteoglycans. They can induce the mechanotransduction process, such as activation of the integrin-Rho/p38 MAPK/ERK pathway, resulting in cellular responses that are involved in pathogenesis and altered bidirectional signaling between leiomyoma cells and the ECM. ECM accumulation is affected by growth factors (TGF-β, activin-A and PDGF), cytokines (TNF-α), steroid hormones (estrogen and progesterone) and microRNAs (miR-29 family, miR-200c and miR-93/106b). Among these, TGF-βs (1 and 3) and activin-A have been suggested as key players in the accumulation of excessive ECM (fibrosis) in leiomyoma. The presence of elevated levels of ECM and myofibroblasts in leiomyoma supports the fibrotic character of these tumors. Interestingly, ECM may serve as a reservoir of profibrotic growth factors and enhance their activity by increasing their stability and extending their duration of signaling. At present, several classes of compounds, including gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate), GnRH antagonist (cetrorelix acetate), selective progesterone receptor modulators (ulipristate acetate and asoprisnil), antiprogestin (mifepristone) and natural compounds like vitamin D and resveratrol have been studied as medical treatments that target ECM in uterine leiomyoma.
Although several types of drugs (mostly antiproliferative agents) are available for leiomyoma treatment, none of them were introduced specifically as antifibrotic agents. In light of its critical role in the process of fibrosis in leiomyoma, we propose that ECM should be considered as a crucial target for future therapeutics. Thus, the introduction of drugs that are specifically antifibrotic could be a good solution to control abnormal leiomyoma growth and associated clinical symptoms. The antifibrotic compounds can be introduced based on their ability to regulate ECM components and their receptors, as well as growth factors, cytokines, steroid hormones and their corresponding receptors and intracellular signaling pathways, as well as microRNAs, involved in ECM production in leiomyoma.
子宫肌瘤（也称为纤维瘤或肌瘤）是生育期妇女最常见的良性子宫肿瘤。它通常不会致命，但会产生严重的临床症状，包括过度子宫出血、盆腔疼痛或压迫、不孕和妊娠并发症。由于缺乏有效的医学治疗方法，手术一直是这种肿瘤治疗的明确选择。
细胞外基质（ECM）的积累和重塑被认为是纤维性疾病（如子宫肌瘤）的关键。事实上，ECM 在形成肌瘤的大部分结构中起着重要作用，而这些肿瘤中富含 ECM 的刚性结构被认为是异常出血和盆腔疼痛的原因。因此，更好地了解 ECM 的积累和重塑对于开发治疗子宫肌瘤的新疗法至关重要。
在 PubMed 和 Google Scholar 上搜索了所有发表的英文原创文章和综述文章/章节，内容涉及 ECM 以及针对子宫肌瘤的医学治疗，截至 2017 年 5 月。
本综述讨论了 ECM 在肌瘤发病机制中的作用，以及目前和未来针对 ECM 直接或间接的医学治疗方法。子宫肌瘤的特征是胶原蛋白、纤维连接蛋白、层粘连蛋白和蛋白聚糖水平升高。它们可以诱导机械转导过程，例如整合素-Rho/p38 MAPK/ERK 途径的激活，导致参与发病机制和肌瘤细胞与 ECM 之间双向信号改变的细胞反应。ECM 的积累受生长因子（TGF-β、激活素-A 和 PDGF）、细胞因子（TNF-α）、甾体激素（雌激素和孕激素）和 microRNAs（miR-29 家族、miR-200c 和 miR-93/106b）的影响。其中，TGF-βs（1 和 3）和激活素-A 被认为是肌瘤中过量 ECM（纤维化）积累的关键因子。肌瘤中 ECM 和肌成纤维细胞水平升高支持这些肿瘤的纤维化特征。有趣的是，ECM 可能作为致纤维化生长因子的储存库，并通过增加其稳定性和延长信号持续时间来增强其活性。目前，已经研究了几类化合物，包括促性腺激素释放激素（GnRH）激动剂（亮丙瑞林醋酸酯）、GnRH 拮抗剂（醋酸西曲瑞克）、选择性孕激素受体调节剂（醋酸乌利司他、阿索普里斯尼尔）、抗孕激素（米非司酮）和天然化合物如维生素 D 和白藜芦醇，作为针对子宫肌瘤 ECM 的医学治疗方法。
尽管有多种类型的药物（主要是抗增殖剂）可用于治疗子宫肌瘤，但没有一种药物是专门作为抗纤维化药物引入的。鉴于其在子宫肌瘤纤维化过程中的关键作用，我们建议将 ECM 视为未来治疗的一个关键靶点。因此，引入专门的抗纤维化药物可能是控制异常肌瘤生长和相关临床症状的一个很好的解决方案。抗纤维化化合物可以根据其调节 ECM 成分及其受体的能力，以及生长因子、细胞因子、甾体激素及其相应受体和细胞内信号通路，以及参与肌瘤 ECM 产生的 microRNAs 来引入。
