Regulation of primary metastasis in high grade serous ovarian cancer

高级别浆液性卵巢癌原发转移的调节

基本信息

批准号：
10368940
负责人：
Tova Bergsten
金额：
$ 5.18万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-16 至 2025-05-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368940
关键词：
Address Adrenergic Agents Adverse effects Anabolism Automobile Driving CRISPR/Cas technology Cancer Biology Cancer Patient Cells Chemicals Chemoprevention Clinical Clinical Management Coculture Techniques Communication Cues Data Development Diagnosis Disease Disease Progression Distant Metastasis Early Intervention Epithelial Epithelial Cells Event FDA approved Goals Human Invaded Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Mediator of activation protein Molecular Mus Mutation Neoplasm Metastasis Norepinephrine Osteonectin Outcome Ovarian Ovary PI3K/AKT Pathway interactions Patient Care Patients Peritoneal Pharmaceutical Preparations Pharmacology Physicians Production Prognosis Propranolol Radiation therapy Refractory Regulation Rest Role Scientist Series Serous Signal Transduction Soil Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization System TP53 gene Techniques Testing Time Training Translating Tube Tumor Promoters Tumor Suppressor Proteins Up-Regulation Woman Xenograft procedure advanced disease antagonist beta-2 Adrenergic Receptors beta-adrenergic receptor clinical practice cost drug repurposing expectation experimental study high risk improved improved outcome inhibitor insight malignant phenotype mass spectrometric imaging migration neoplastic cell novel strategies ovarian neoplasm overexpression paracrine precision medicine prevent receptor release factor response small hairpin RNA standard of care tumor tumor progression tumorigenic

项目摘要

Project Summary/Abstract High grade serous ovarian cancer (HGSOC) is both the most common and most lethal ovarian cancer histotype. Though HGSOC has been long thought to originate in the ovary, recent evidence now suggests that HGSOC precursor lesions in fact originate in the fallopian tube. Further, select dysplastic cells from the fallopian tube disseminate from these precursor lesions and follow a variety of local migratory cues in order to colonize the ovary and establish a primary HGSOC tumor. The ovary seems to facilitate the expansion and spread of the ovary to the rest of the peritoneal space. Though this phenomenon is well documented, the molecular mechanisms that drive the initial dissemination of dysplastic fallopian tube cells to the ovary are poorly understood. To address this, our group has developed a new imaging mass spectrometry technique that has allowed for unprecedented insight into the paracrine factors that create a pro-metastatic niche and allow for the migration of fallopian tube cells toward the ovary. Using this technique, we determined that co-culture of murine ovary explants with dysplastic tubal cells leads to consistent increases in norepinephrine secretion from the ovary, later found to be produced by the ovary itself. This is significant, as norepinephrine is an established tumor promoter in advanced disease, and ovarian cancer patients taking β-blockers that interfere with norepinephrine signals typically have improved clinical outcomes. However, the role of norepinephrine in tumor development is largely unknown. Given the wide availability, low cost, and minimal adverse effects of β- blockers, should norepinephrine similarly enhance the development of HGSOC this may provide opportunity for early intervention and/or chemoprevention in high-risk patients. Given the potential to directly impact clinical practice, it is essential to further dissect both the mechanisms that direct norepinephrine biosynthesis, as well as the downstream effects of norepinephrine during HGSOC development. Through the experiments detailed in this proposal, we will gain valuable insight into these events in hopes of either preventing or delaying HGSOC development in high-risk patients.

项目摘要/摘要高级浆液卵巢癌（HGSOC）既是最常见，最致命的卵巢癌组织类型。尽管长期以来人们一直认为HGSOC起源于卵巢，但最近的证据表明实际上，HGSOC前体病变起源于输卵管。此外，从输卵管从这些前体病变中传播，并遵循各种局部迁移提示定居卵巢并建立原发性HGSOC肿瘤。卵巢似乎有助于扩张和将卵巢扩散到其余的腹膜空间。尽管这种现象已得到充分记录，但驱动卵巢发育不良的输卵管细胞初始传播的分子机制是理解不佳。为了解决这个问题，我们的小组开发了一种新的成像质谱技术允许对产生亲构的旁分泌因素的前所未有的见解，并允许为了将输卵管细胞迁移到卵巢。使用这种技术，我们确定了带有发育异常小管细胞的鼠卵巢外植体可导致去甲肾上腺素分泌的一致增加后来发现卵巢是由卵巢本身产生的。这很重要，因为去甲肾上腺素是已建立的晚期疾病中的肿瘤启动子和卵巢癌患者服用β受体阻滞剂去甲肾上腺素信号通常会改善临床结果。但是，去甲肾上腺素在肿瘤中的作用发展在很大程度上是未知的。鉴于β-的广泛可用性，低成本和最小的不利影响阻滞剂，如果去甲肾上腺素同样可以增强HGSOC的发展，这可能会提供机会对于高危患者的早期干预和/或化学预防。考虑到直接影响临床的潜力实践，必须进一步剖析直接去甲肾上腺素生物合成的机制作为HGSOC发育过程中去甲肾上腺素的下游影响。通过详细的实验在此提案中，我们将对这些事件获得宝贵的见解，以期防止或延迟高危患者的HGSOC发育。