子宫内膜癌保育治疗孕激素耐药分子机制的相关研究进展

Research progress on the molecular mechanisms involving in progesterone resistance of the fertility-sparing treatment in endometrial cancer

大剂量高效孕激素是年轻有生育需求的早期子宫内膜癌患者保留生育功能的标准治疗方案,但相当一部分患者存在原发或继发性孕激素治疗不敏感,造成治疗时间延长,不良反应增加,甚至疾病进展,严重影响保留生育功能效果。因此,解析探讨子宫内膜癌孕激素治疗不敏感/耐药的分子机制对于临床治疗有重大指导意义。孕激素受体介导的信号通路是孕激素发挥抗肿瘤作用的主要途径,包括孕激素受体、相关共作用信号分子、转录因子以及肿瘤-代谢-免疫微环境等可协同干扰孕激素受体信号通路。本文就目前孕激素治疗不敏感/耐药的分子机制的研究进展作一综述,系统阐述孕激素受体相关信号通路中影响子宫内膜癌孕激素敏感性的关键因素,以期为进一步解析子宫内膜癌孕激素不敏感/耐药的可能机制,为子宫内膜癌合理、安全、有效地保育治疗提供理论依据,为孕激素治疗不敏感的子宫内膜癌患者寻求新的治疗方法奠定基础。

High-dose progestin therapy has been used as a standard fertility-sparing treatment for young women with early endometrial cancer(EC)who have a strong desire to preserve fertility.However,a considerable number of patients are suffering from de novo or acquired progesterone insensitivity that severely inhibits the therapeutic efficacy,including extending treatment cycles,increasing adverse effects,or even contributing to tumor progression.Therefore,figuring out molecular mechanisms involved in EC progesterone resistance is of great significance for clinical treatment.The antitumor activity of progestin mainly relies on its binding to progesterone receptors(PR)and downstream PR signaling pathways.Many factors,such as progesterone receptors,steroid receptor co-regulators,transcriptional factors,and tumormetabolism-immunity microenvironment,can synergistically interfere with PR signaling pathway in different layers.This review summarizes current known mechanisms of progesterone resistance,elaborates on key factors in regulating progesterone responsiveness of PR signaling pathway,and aims to systematically analyze possible molecular mechanisms of EC progesterone resistance,provide theoretical basis for an optimal conservative treatment strategy,and establish a foundation for seeking new treatments for progesterone resistant patients.