Role of Age-Related Changes in the Tumor Microenvironment on Ovarian Cancer Progression

项目总结/摘要 上皮性卵巢癌（EOC）是最致命的妇科疾病，最常见于女性 绝经后，年龄55-64岁（中位数，63岁）。尽管EOC患者的生存率有所改善， 在过去的三十年里，对于年轻女性来说，老年患者的情况并非如此。两大影响因素 预后和存活率是转移和复发，并且已知这些与衰老正相关。的 年龄对卵巢癌发生、发展和复发的影响机制尚不清楚， 定义了我们将使用EOC的异种移植大鼠模型来帮助填补这些知识空白，并确定衰老如何影响 EOC的发展和进步。基于有限的先前研究，我们假设基因调控途径和 老年与年轻肿瘤微环境（TME）的代谢修饰-重点是ECM -有助于 更具有侵袭性的卵巢癌表型我们的具体目标是：1）确定基因表达和细胞 来自年轻和老年（雌激素暂停）大鼠的腹部脂肪组织的代谢谱;和2）确定基因表达 和卵巢癌间质组织的细胞代谢谱。纵向研究设计将允许分析 在整个癌症发展和进展过程中，有三个目标时间点，包括在 癌症开始、癌症进展期间和复发时。考虑到卵巢癌细胞的强烈倾向， 嵌入并生长在网膜脂肪中，我们将特别关注这种脂肪组织TME在衰老过程中的变化（以及 大鼠雌激素暂停）和疾病过程中。我们将确定代谢和RNAseq基因表达谱 没有恶性肿瘤的年轻和老年大鼠之间的差异，然后检查年龄特异性差异在上下文中如何变化 癌症的发展。生物信息学分析将确定是否存在特定基因本体论术语的富集， 差异表达基因之间的通路。我们希望这项研究的结果将提供数据，以支持 通过揭示新的靶点来帮助预防转移和/或复发的更大的研究，可以在 临床前模型，旨在转化为老年和绝经后EOC患者的临床试验。

Project Summary/Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecologic disease that is most commonly diagnosed in women postmenopausal, aged 55-64 years (median, 63). Although survival of patients with EOC has shown some improvement over the past three decades for younger women, the same is not true for older patients. Two major factors that impact prognosis and survival are metastasis and recurrence, and these are known to be positively related to aging. The mechanisms that underlie the influence of age on ovarian cancer development, progression and recurrence are poorly defined. We will use a xenograft rat model of EOC to help fill these gaps in knowledge and define how aging impacts EOC development and progression. Based on limited prior studies, we hypothesize that the gene regulation pathways and metabolic modification of aged versus younger tumor microenvironment (TME) – with a focus on the ECM – contribute to a more aggressive ovarian cancer phenotype. Our specific aims are: 1) to determine gene expression and cellular metabolic profiles of abdominal fat tissues from young and aged (estropause) rats; and 2) to determine gene expression and cellular metabolic profiles of ovarian cancer stroma tissues. The longitudinal study design will permit analysis throughout the course of cancer development and progression with three targeted timepoints, including analysis prior to cancer initiation, during cancer progression and at recurrence. Given the strong propensity for ovarian cancer cells to embed and grow in omental fat, we will specifically focus attention on changes in this fat tissue TME during aging (and estropause in rat) and over the course of disease. We will determine how metabolic and RNAseq gene expression profiles differ between young and aged rats without malignancy and then examine how age-specific differences vary in the context of cancer progression. Bioinformatic analyses will determine if there is enrichment of particular gene ontology terms and pathways among the differentially expressed genes. We expect findings from this study will provide data to support a larger study by revealing new targets to aid prevention of metastasis and/or recurrence which can be further evaluated in preclinical models with the objective of translation to clinical trials for older and postmenopausal EOC patients.