Adrenergic modulation of ovarian cancer progression and chemoresistance

项目摘要/摘要 越来越多的证据表明，压力在心血管疾病、癌症和其他疾病中扮演着重要角色。 我们小组和其他人的研究表明，慢性压力或抑郁等心理状态可能会 加速现有肿瘤的生长，促进化疗耐药性。重要的是，有相当数量的 卵巢癌患者在临床上存在抑郁或缺乏社会支持。这些情绪状态一直是 与交感神经系统的持续激活和存活率下降有关。我们的团队已经 研究表明，交感神经系统的激活会导致去甲肾上腺素和 肾上腺素在肿瘤微环境中的作用与卵巢癌的进展。 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 卵巢癌相关基因和抑制顺铂诱导的卵巢癌细胞凋亡。给定 BRCA1调节的DNA修复机制在顺铂反应、肾上腺素能调节中的重要性 BRCA1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 心理治疗。然而，这些观察结果背后的潜在机制并不完全清楚。在……里面 在这个实验中，我们将通过实现以下目标来检验这一假设：1)剖析肾上腺素能 卵巢癌细胞中的信号转导和2)探索感受到的压力和抑郁之间的联系 肿瘤儿茶酚胺、DNA损伤和BRCA1蛋白表达的症状学。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。这项建议将为进一步研究精度奠定基础。 将心理风险因素与潜在的肿瘤生物学联系起来的医学。

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.