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:10229162
- 负责人:
- 金额:$ 5.1万
- 依托单位:
- 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:
- 关键词:AddressAdrenergic AgentsAdverse effectsAnabolismAutomobile DrivingBiologicalCRISPR/Cas technologyCancer BiologyCancer PatientCellsChemicalsChemopreventionClinicalClinical ManagementCoculture TechniquesCommunicationCuesDataDevelopmentDiagnosisDiseaseDisease ProgressionDistant MetastasisEarly InterventionEpithelialEpithelial CellsEventFDA approvedGoalsHumanImageInvadedLesionMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of ovaryMammalian OviductsMass Spectrum AnalysisMediator of activation proteinMolecularMusMutationNeoplasm MetastasisNorepinephrineOsteonectinOutcomeOvarianOvaryPI3K/AKTPathway interactionsPatient CarePatientsPeritonealPharmaceutical PreparationsPharmacologyPhysiciansProductionPrognosisPropranololRadiation therapyRefractoryRegulationRestRoleScientistSeriesSerousSignal TransductionSoilSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSystemTP53 geneTechniquesTestingTimeTrainingTranslatingTubeTumor PromotersTumor Suppressor ProteinsUp-RegulationWomanXenograft procedureadvanced diseasebeta-2 Adrenergic Receptorsbeta-adrenergic receptorclinical practicecostdrug repurposingexpectationexperimental studyhigh riskimprovedimproved outcomeinhibitor/antagonistinsightmalignant phenotypemigrationneoplastic cellnovel strategiesovarian neoplasmoverexpressionparacrineprecision medicinepreventreceptorrelease factorresponsesmall hairpin RNAstandard of caretumortumor progressiontumorigenic
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.
项目总结/摘要
高级别浆液性卵巢癌(HGSOC)是最常见且最致命的卵巢癌
组织型虽然HGSOC一直被认为起源于卵巢,但最近的证据表明,
HGSOC前驱病变实际上起源于输卵管。此外,从细胞中选择发育异常细胞。
输卵管从这些前驱病变扩散,并遵循各种局部迁移线索,
定植于卵巢并建立原发性HGSOC肿瘤。卵巢似乎促进了扩张,
卵巢扩散到腹膜间隙的其余部分。虽然这种现象是有据可查的,
促使发育不良的输卵管细胞最初播散到卵巢的分子机制是
不太了解。为了解决这个问题,我们的团队开发了一种新的成像质谱技术,
允许前所未有的洞察旁分泌因素,创造一个促转移的利基,并允许
用于输卵管细胞向卵巢迁移。使用这种技术,我们确定,
具有发育不良输卵管细胞的小鼠卵巢外植体导致去甲肾上腺素分泌持续增加,
卵巢,后来发现是由卵巢本身产生的。这是重要的,因为去甲肾上腺素是一种公认的
晚期疾病中的肿瘤促进剂,以及服用β受体阻滞剂的卵巢癌患者,
去甲肾上腺素信号通常具有改善的临床结果。然而,去甲肾上腺素在肿瘤中的作用
发展基本上是未知的。鉴于β-羟考酮的广泛可用性、低成本和最小的不良反应,
阻断剂,去甲肾上腺素应该同样促进HGSOC的发展,这可能提供机会
用于高危患者的早期干预和/或化学预防。考虑到可能直接影响临床
实践中,有必要进一步剖析直接去甲肾上腺素生物合成的机制,以及
作为HGSOC发展过程中去甲肾上腺素的下游效应。通过详细的实验
在这一建议中,我们将获得对这些事件的有价值的洞察力,希望能够阻止或推迟这些事件的发生
高危患者中HGSOC的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Tova Bergsten', 18)}}的其他基金
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
- 批准号:
10368940 - 财政年份:2021
- 资助金额:
$ 5.1万 - 项目类别:
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
- 批准号:
10608098 - 财政年份:2021
- 资助金额:
$ 5.1万 - 项目类别:
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