Adrenergic modulation of ovarian cancer progression and chemoresistance

卵巢癌进展和化疗耐药的肾上腺素调节

• 批准号: 9770783
• 负责人: GUILLERMO N ARMAIZ-PENA
• 金额: $ 7.57万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9770783
• 关键词: Adenosine Monophosphate; Adrenergic Agents; Affect; Aftercare; Apoptosis; Attenuated; Automobile Driving; BRCA1 Protein; BRCA1 gene; Biological; Biology; Breast; CDKN1C gene; Cancer Biology; Cancer Center; Cancer Patient; Cancer cell line; Cancer-Predisposing Gene; Cardiovascular Pathology; Catecholamines; Cells; Chronic stress; Cisplatin; Clinical; Code; Cognitive Therapy; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclin-Dependent Kinase Inhibitor; DNA Damage; DNA Nucleotidylexotransferase; DNA Repair; Data; Depressed mood; Disease; Distress; Emotional; Epinephrine; Exhibits; Future; Gene Expression; Generations; Genes; Genomics; Goals; Growth; Health Sciences; Hormones; Infiltration; Inflammatory; Joints; Label; Lead; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Messenger RNA; Nerve; Norepinephrine; Outcome; Ovarian; Ovarian Serous Adenocarcinoma; Pathway interactions; Patient Self-Report; Patients; Periodicity; Platinum; Regulation; Research; Resistance; Risk; Risk Factors; Role; Signal Transduction; Social support; Stress; Sympathetic Nervous System; Testing; Transcriptional Regulation; Tumor Biology; Tumor Initiators; Universities; Work; base; cancer biomarkers; cancer cell; chemotherapy; chronic depression; cytokine; depressive symptoms; experimental study; macrophage; malignant breast neoplasm; neoplastic cell; outcome forecast; perceived stress; precision medicine; protein expression; psychologic; psychosocial; response; social; symptomatology; transcriptome; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT There is growing evidence for the role of stress in cardiovascular pathologies, cancer, and other diseases. Work from our group and others has shown that psychological states such as chronic stress or depression may accelerate growth of existing tumors and promote chemoresistance. Importantly, a significant number of ovarian cancer patients are clinically depressed or lack social support. These emotional states have been linked to sustained activation of the sympathetic nervous system and decreased survival. Our group has shown that activation of the sympathetic nervous system leads to increased levels of norepinephrine and epinephrine in the tumor microenvironment and ovarian cancer progression by inducing pro-tumoral pathways. Our preliminary data in cancer cell lines suggest that norepinephrine significantly changes the expression of genes implicated in ovarian cancer and attenuates cisplatin-induced ovarian cancer cell apoptosis. Given the importance of BRCA1-regulated DNA repair mechanisms in cisplatin response, adrenergic regulation of BRCA1 expression in tumors may also impact ovarian cancer progression and resistance to platinum-based therapy. However, the underlying mechanisms behind these observations are not completely understood. In this pilot we will test this hypothesis by achieving the following aims: 1) To dissect the effects of adrenergic signaling in ovarian cancer cells and 2) To explore the association between perceived stress and depressive symptomatology with tumor catecholamines, DNA damage, and BRCA1 protein expression. This proposal provides a unique approach to explore the link between stress and ovarian cancer outcomes at both the tumor level and the patient level. This proposal will provide the groundwork for additional research on precision medicine by linking psychological risk factors with underlying tumor biology.

项目总结/摘要 越来越多的证据表明压力在心血管疾病、癌症和其他疾病中的作用。 我们小组和其他人的工作表明，心理状态，如慢性压力或抑郁， 加速现有肿瘤的生长并促进化学抗性。重要的是， 卵巢癌患者临床上抑郁或缺乏社会支持。这些情绪状态 与交感神经系统的持续激活和生存率下降有关。我们集团 显示交感神经系统的激活导致去甲肾上腺素水平的增加， 肾上腺素在肿瘤微环境和卵巢癌的进展诱导促肿瘤途径。 我们在癌细胞系中的初步数据表明，去甲肾上腺素显著改变了 与卵巢癌有关的基因，并减弱顺铂诱导的卵巢癌细胞凋亡。鉴于 BRCA 1调节的DNA修复机制在顺铂反应、肾上腺素能调节 BRCA 1在肿瘤中的表达也可能影响卵巢癌的进展和对铂类药物的耐药性。 疗法然而，这些观察结果背后的潜在机制尚未完全理解。在 本试验将通过实现以下目标来检验这一假设：1）解剖肾上腺素能神经递质的作用， 卵巢癌细胞中的信号传导; 2）探索感知压力与抑郁之间的关系 肿瘤学与肿瘤儿茶酚胺、DNA损伤和BRCA 1蛋白表达。这项建议 提供了一种独特的方法来探索压力和卵巢癌结果之间的联系， 水平和患者水平。这一提议将为进一步研究精确度奠定基础 将心理风险因素与潜在的肿瘤生物学联系起来。