Ovarian Inflammaging as a Mechanism for Ovarian Cancer

卵巢炎症是卵巢癌的机制

• 批准号: 10532678
• 负责人: Shweta S. Dipali
• 金额: $ 4.2万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532678
• 关键词: 3-Dimensional; Adhesions; Age; Aging; Animals; Architecture; Biological Markers; Biomechanics; Blocking Antibodies; Cell Adhesion; Cell Line; Cell Proliferation; Cell Transplantation; Collagen; Contraceptive methods; DNA Damage; Data; Detection; Development; Diagnosis; Disseminated Malignant Neoplasm; Dose; Elderly; Environment; Epithelial; Epithelial Cells; Exposure to; Extracellular Matrix; Fibrosis; Follicular Fluid; Gene Mutation; Homing; Human; Hydrogels; In Vitro; Incidence; Inflammaging; Inflammatory; KDR gene; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mass Spectrum Analysis; Mesenchymal; Mus; Neoplasm Metastasis; Neoplastic Cell Transformation; Oral; Oral Contraceptives; Ovarian; Ovarian Serous Adenocarcinoma; Ovarian Tissue; Ovarian aging; Ovary; Ovulation; Ovulation Inhibition; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Postmenopause; Pregnancy; Property; Recombinants; Reproductive Sciences; Research; Risk; Risk Factors; Role; Series; Serous; Signal Pathway; Testing; Tissues; Transplantation; Tumor Expansion; Tumor-Derived; Vascular Endothelial Growth Factors; Woman; Work; Xenograft procedure; advanced maternal age; age effect; age related; body system; cancer cell; cancer initiation; cell motility; cytokine; female reproductive system; in vivo; inhibitor; insight; macrophage; neoplastic cell; recruit; reproductive; reproductive senescence; therapeutic target; transcriptome; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY High-grade serous ovarian carcinoma (HGSOC) is the most lethal cancer of the female reproductive system with less than 50% of patients surviving 5 years after diagnosis. A woman’s total lifetime number of ovulations is a key risk factor for developing ovarian cancer, and factors that repress ovulation including use of oral contraceptives significantly reduce HGSOC incidence. Despite the association with ovulation, HGSOC typically presents as late-stage, metastatic cancer in post-menopausal women who are no longer ovulating. Therefore, a major question in the field is: how do ovulation during a woman’s reproductive prime and the aging ovary post- menopause contribute to ovarian cancer development. Here, I propose two distinct aspects of the aging ovarian microenvironment that promote HGSOC initiation and pathogenesis. First, follicular fluid, which becomes fibro- inflammatory with advanced reproductive age, triggers tumor initiation in the fallopian tube epithelium (FTE). Second, changes to the composition and biomechanics of the aging ovarian extracellular matrix (ECM) allow for enhanced tumor cell adhesion and invasion. Recent data suggest that HGSOC tumors arise from the FTE, and exposure to follicular fluid results in DNA damage in FTE cells both in vivo and in vitro. However, the direct effect of reproductive aging on FTE tumorigenesis has not been examined. Work from our lab has identified a series of fibro-inflammatory cytokines that increase in human follicular fluid with advanced reproductive age, including VEGF which has roles in HGSOC metastasis and is involved in tumor initiation in other organ systems. In Aim 1 of this proposal, I will test the hypothesis that follicular fluid induces neoplastic transformation of the FTE in an age-dependent manner, through the action of candidate cytokine VEGF. I will treat FTE cell lines with human follicular fluid across an aging continuum or a dose-curve of recombinant-human VEGF to determine effects to cell proliferation, DNA damage, oxidative stress, and global gene expression. After tumor initiation in the FTE, tumor cells migrate to the ovary for expansion. Work from our lab has characterized significant changes to the composition of the ovarian ECM with advanced reproductive age including increased levels of collagen I and III, which increase tissue stiffness. HGSOC cells have been shown to favor a 3D collagen-rich matrix for expansion and stiffer matrices are known to increase cancer cell motility. In Aim 2, I will determine the mechanism by which the tissue environment of the aging ovarian ECM promotes HGSOC pathogenesis by investigating the independent functions of ECM composition and ovarian tissue stiffness on HGSOC cell adhesion and invasion. To this end, I will assess in vitro HGSOC cell adhesion and invasion on hydrogels that recapitulate the stiffness and collagen abundance of the aging ovary. Furthermore, I will evaluate HGSOC cell adhesion and invasion in reproductively young and old decellularized mouse ovaries ex vivo, as well as an in vivo after transplantation into reproductively young and old hosts. Taken together, these studies will provide mechanistic insight into how ovulation and the aging ovary contribute to HGSOC and identify key pathways as therapeutic targets.

项目概要 高级别浆液性卵巢癌（HGSOC）是女性生殖系统最致命的癌症， 诊断后 5 年内存活的患者不到 50%。 发生卵巢癌的关键危险因素，以及抑制排卵的因素，包括使用口服避孕药 尽管与排卵有关，但避孕药可显着降低 HGSOC 的发生率。 在不再排卵的绝经后女性中表现为晚期转移性癌症。 该领域的主要问题是：女性生育高峰期的排卵和生育后卵巢的老化如何影响排卵？ 在此，我提出了卵巢老化的两个不同方面。 促进 HGSOC 启动和发病机制的微环境首先是卵泡液，它变成纤维。 高龄生育期的炎症会引发输卵管上皮 (FTE) 肿瘤的发生。 其次，老化的卵巢细胞外基质（ECM）的成分和生物力学的变化使得 增强的肿瘤细胞粘附和侵袭。最近的数据表明 HGSOC 肿瘤源自 FTE，并且 暴露于卵泡液会导致体内和体外 FTE 细胞的 DNA 损伤。 我们实验室的工作尚未研究生殖衰老对 FTE 肿瘤发生的影响。 随着生育年龄的增长，人类卵泡液中纤维炎症细胞因子的增加，包括 VEGF 在 HGSOC 转移中发挥作用，并参与其他器官系统中的肿瘤发生。 在这个提议中，我将检验以下假设：卵泡液会在 FTE 中诱导肿瘤性转化。 年龄依赖性方式，通过候选细胞因子 VEGF 的作用，我将用人类治疗 FTE 细胞系。 跨越衰老连续体或重组人 VEGF 剂量曲线的卵泡液，以确定对 FTE 中肿瘤发生后，细胞增殖、DNA 损伤、氧化应激和全局基因表达。 我们实验室的工作表明肿瘤细胞迁移到卵巢发生显着变化。 高龄生育期卵巢 ECM 的组成包括胶原蛋白 I 和 III 水平的增加， HGSOC 细胞已被证明有利于富含 3D 胶原蛋白的基质进行扩张。 已知更硬的基质会增加癌细胞的运动性。在目标 2 中，我将确定其机制。 衰老卵巢 ECM 的组织环境促进 HGSOC 发病机制 ECM 成分和卵巢组织硬度对 HGSOC 细胞粘附和侵袭的独立作用。 为此，我将评估体外 HGSOC 细胞在水凝胶上的粘附和侵袭，以重现刚度 此外，我将评估 HGSOC 细胞的粘附和侵袭。 具有生殖能力的年轻和年老脱细胞小鼠卵巢离体以及移植后的体内 总而言之，这些研究将为年轻和年老宿主的繁殖提供机制上的见解。 排卵和卵巢老化有助于 HGSOC 并确定关键途径作为治疗目标。