PO.PR01.04 · 预防研究
肥胖介导的细胞外囊泡分泌作为子宫内膜癌发生与进展的可靶向驱动因素
Obesity-mediated extracellular vesicle secretion as a targetable driver of endometrial cancer initiation and progression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：子宫内膜癌（EC）是美国最常见的妇科恶性肿瘤，其中约 57% 的病例归因于肥胖。将肥胖与 EC 发生联系起来的分子机制仍不明确。新兴证据提示，肥胖增强细胞外囊泡（EV）分泌并改变 EV 相关的致癌信号传导。本研究调查肥胖介导的 EV 失调在脂肪、子宫和 EC 组织中的情况，并探索其在早期 EC 发病机制、生物标志物开发和治疗干预中的作用。
方法：通过高脂饮食（HFD；45% 或 60% kcal 脂肪）在免疫功能正常的小鼠中诱导子宫内膜增生和 EC，持续 25 周。使用 LC-MS/MS 进行分子谱分析。通过纳米颗粒追踪分析（NTA）定量 EV 浓度和大小，并通过透射电子显微镜（TEM）进行可视化。在来自 HFD 处理小鼠和肥胖 EC 患者的组织中，通过免疫组织化学、ELISA 和 RT-PCR 评估 TMEM205、STAT5、FAS 和抑癌基因 PIAS3 的表达。进一步的研究在接受化疗或免疫治疗的异种移植模型中评估了 EV 介导的肿瘤进展和治疗反应。
结果：与非肥胖对照相比，肥胖 EC 患者样本在脂肪和子宫组织中表现出显著增加的 EV 分泌和致癌蛋白的上调。在 HFD 处理的小鼠中，体重升高、腹部脂肪堆积、子宫角增大和慢性炎症与子宫内膜增生和 EC 发生相关。这些表型与 EV 分泌增加、TMEM205、FAS 和 STAT5 上调以及 PIAS3 显著下调相关。HFD 诱导的 EV 携带与血清葡萄糖和脂质水平升高及免疫谱改变相关的致癌蛋白。肥胖条件下的 EV 还促进了侵袭性 EC 进展以及对化疗和免疫治疗的耐药性。使用小分子 EV 分泌抑制剂 DAP-5 治疗，可显著降低 HFD 喂养小鼠的体重、脂肪堆积和 EV 输出，并恢复正常子宫形态，同时抑制 EV 相关的致癌信号传导。
结论：肥胖介导的 EV 分泌是 EC 发生和进展的主要驱动因素。靶向 EV 生物发生是肥胖相关 EC 的一种有前景的预防和治疗策略。这些临床前研究结果为推进 EV 靶向干预（包括旨在预防肥胖驱动的 EC 发生的首次人体试验）提供了强有力的理论依据。
查看英文原文 English abstract
Introduction: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, with obesity accounting for approximately 57% of cases. The molecular mechanisms linking obesity to EC initiation remain poorly defined. Emerging evidence suggests that obesity enhances extracellular vesicle (EV) secretion and alters EV-associated oncogenic signaling. This study investigates obesity-mediated EV dysregulation in adipose, uterine, and EC tissues and explores its role in early EC pathogenesis, biomarker development, and therapeutic intervention.
Methods: Endometrial hyperplasia and EC were induced in immunocompetent mice using high-fat diets (HFD; 45% or 60% kcal fat) for 25 weeks. Molecular profiling was conducted using LC-MS/MS. EV concentration and size were quantified by nanoparticle tracking analysis (NTA) and visualized by transmission electron microscopy (TEM). Expression of TMEM205, STAT5, FAS, and the tumor suppressor PIAS3 was assessed by immunohistochemistry, ELISA, and RT-PCR in tissues from HFD-treated mice and obese EC patients. Additional studies evaluated EV-mediated tumor progression and treatment response in xenograft models receiving chemotherapy or immunotherapy.
Results: Obese EC patient samples exhibited significantly increased EV secretion and upregulation of oncogenic proteins in adipose and uterine tissues compared to non-obese controls. In HFD-treated mice, elevated body weight, abdominal adiposity, uterine horn enlargement, and chronic inflammation correlated with endometrial hyperplasia and EC initiation. These phenotypes were associated with increased EV secretion, upregulation of TMEM205, FAS, and STAT5, and marked downregulation of PIAS3. HFD-induced EVs carried oncogenic proteins linked to elevated serum glucose and lipid levels and altered immune profiles. EVs from obese conditions also promoted aggressive EC progression and resistance to chemotherapy and immunotherapy. Treatment with the small-molecule EV secretion inhibitor DAP-5 significantly reduced body weight, adipose accumulation, and EV output in HFD-fed mice and restored normal uterine morphology while suppressing EV-associated oncogenic signaling.
Conclusion: Obesity-mediated EV secretion is a major driver of EC initiation and progression. Targeting EV biogenesis represents a promising preventive and therapeutic strategy for obesity-associated EC. These preclinical findings provide a strong rationale for advancing EV-targeted interventions, including first-in-human trials aimed at preventing obesity-driven EC development.
利益披露 Disclosure
L. Chakrapani, None..
K. Dorayappan, None..
G. Yadagiri, None..
S. Sundaram, None..
G. S. Vendrell, None..
T. Sakaue, None..
J. Velasquez, None..
X. Washington Ramesh, None..
T. Muthusamy, None..
C. M. Cosgrove, None..
D. E. Cohn, None..
D. M. O'Malley, None..
S. Karuppaiyah, None.