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

项目摘要/摘要 上皮性卵巢癌(EOC)是女性中最常见的一种致命的妇科疾病。 绝经后，55岁-(中位数，63岁)。尽管卵巢癌患者的存活率有所改善 在过去的三十年里，年轻女性的情况并非如此，老年患者的情况就不同了。影响的两个主要因素 预后和存活率是转移和复发，而且已知这些与年龄呈正相关。这个 年龄对卵巢癌发生、发展和复发的影响机制尚不清楚。 已定义。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，并确定老龄化是如何影响的 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 老年肿瘤微环境(TME)与年轻肿瘤微环境(TME)的代谢修饰--侧重于ECM--贡献 更具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 青年和老年(动情停滞)大鼠腹部脂肪组织的代谢谱；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 在癌症发展和进展的整个过程中，有三个目标时间点，包括在 癌症发生、癌症进展和复发。鉴于卵巢癌细胞有很强的 为了在大网膜脂肪中嵌入和生长，我们将特别关注这种脂肪组织TME在老化过程中的变化(和 大鼠的动情停顿)和整个病程。我们将确定代谢和RNAseq基因表达谱 在年轻和老年非恶性肿瘤大鼠之间的差异，然后检查不同年龄的差异在背景下如何变化 癌症的进展。生物信息学分析将确定是否有特定的基因本体论术语和 差异表达基因之间的通路。我们预计这项研究的结果将提供数据来支持 通过揭示新的靶点来帮助预防转移和/或复发的更大规模的研究，可以在 旨在将老年和绝经后卵巢癌患者转化为临床试验的临床前模型。

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.