PDF(Pubmed)
Abstract：
Uterine fibroids are the most common tumors in females affecting up to 70% of women world-wide, yet targeted therapeutic options are limited. Oxidative stress has recently surfaced as a key driver of fibroid pathogenesis and provides insights into hypoxia-induced cell transformation, extracellular matrix pathophysiology, hypoxic cell signaling cascades, and uterine biology. Hypoxia drives fibroid tumorigenesis through (1) promoting myometrial stem cell proliferation, (2) causing DNA damage propelling transformation of stem cells to tumor initiating cells, and (3) driving excess extracellular matrix (ECM) production. Common fibroid-associated DNA mutations include MED12 mutations, HMGA2 overexpression, and Fumarate hydratase loss of function. Evidence suggests an interaction between hypoxia signaling and these mutations. Fibroid development and growth are promoted by hypoxia-triggered cell signaling via various pathways including HIF-1, TGFβ, and Wnt/β-catenin. Fibroid-associated hypoxia persists due to antioxidant imbalance, ECM accumulation, and growth beyond adequate vascular supply. Current clinically available fibroid treatments do not take advantage of hypoxia-targeting therapies. Growing pre-clinical and clinical studies identify ROS inhibitors, anti-HIF-1 agents, Wnt/β-catenin inhibition, and TGFβ cascade inhibitors as agents that may reduce fibroid development and growth through targeting hypoxia.
摘要：
子宫肌瘤是女性最常见的肿瘤，影响到全世界70%的女性。然而，有针对性的治疗选择是有限的。氧化应激最近已成为肌瘤发病机制的关键驱动因素，并提供了对缺氧诱导的细胞转化的见解。细胞外基质病理生理学，缺氧细胞信号级联，和子宫生物学。缺氧通过（1）促进子宫肌层干细胞增殖驱动肌瘤的发生，(2)引起DNA损伤促进干细胞向肿瘤起始细胞转化,和(3)驱动过量的细胞外基质(ECM)产生。常见的纤维瘤相关DNA突变包括MED12突变，HMGA2过表达,和富马酸水合酶功能丧失。证据表明缺氧信号与这些突变之间存在相互作用。缺氧触发的细胞信号通过多种途径促进纤维的发育和生长，包括HIF-1，TGFβ，和Wnt/β-连环蛋白。由于抗氧化剂失衡，纤维相关的缺氧持续存在，ECM积累，和生长超过足够的血管供应。目前临床上可用的纤维瘤治疗没有利用缺氧靶向治疗。越来越多的临床前和临床研究确定ROS抑制剂，抗HIF-1药物，Wnt/β-连环蛋白抑制，和TGFβ级联抑制剂作为可以通过靶向缺氧来减少肌瘤发育和生长的药物。
