Ovarian Cancer: Mechanisms of Neuroendocrine Regulation

卵巢癌：神经内分泌调节机制

• 批准号: 6928232
• 负责人: ANIL K SOOD
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928232
• 关键词: angiogenesis; angiogenesis factor; athymic mouse; biological models; catecholamine inhibitor; catecholamines; clinical research; cortisol; cytokine; disease /disorder model; female; hormone regulation /control mechanism; human subject; laboratory mouse; neoplasm /cancer blood supply; neoplastic process; neuroendocrine system; ovary neoplasms; patient oriented research; psychological stressor; secretion; stress; vascular endothelial growth factors; women' s health

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death among women with gynecologic malignancies. Due to poor survival of women with epithelial ovarian cancer, identification of factors responsible for accelerated cancer growth may lead to development of novel therapeutic approaches. Stress can elicit alterations of immunological, neurochemical, and endocrinological functions. To date, most of the research dealing with stress and tumor growth has focused on suppressed immunity; however, progressive growth of cancer is influenced by many other factors including blood supply to growing tumors (angiogenesis). There has been little investigation of the effect of stress mediators such as norepinephrine and epinephrine on angiogenesis. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are key factors that can stimulate tumor angiogenesis. We have compelling preliminary data that catecholamines can directly increase the production of pro-angiogenic cytokines such as VEGF and IL-8 by ovarian cancer cells and this effect can be blocked by using inhibitors of beta-adrenergic receptors. This project is designed to examine the effects of stress related mediators (norepinephrine, epinephrine, and cortisol) on secretion of pro-angiogenic cytokines by ovarian cancer cells and their resultant effects on cancer progression. We have designed a series of experiments that will determine the underlying mechanisms and pathways by which stress mediators can achieve these effects. We will also determine the in vivo effects of stress mediators on ovarian cancer growth and angiogenesis, and the effect of specific methods to block these deleterious effects using an in vivo orthotopic mouse model of ovarian cancer metastasis. Findings of this study could lead to identification of novel mechanisms underlying accelerated ovarian cancer growth and therefore may lead to new therapeutic approaches.

描述（由申请人提供）：卵巢癌是妇科恶性肿瘤女性死亡的主要原因。由于上皮卵巢癌的女性的存活不良，因此鉴定导致加速癌症生长的因素可能会导致新型治疗方法的发展。压力会引起免疫，神经化学和内分泌功能的改变。迄今为止，涉及压力和肿瘤生长的大多数研究都集中在抑制免疫力上。然而，癌症的进行性生长受到许多其他因素的影响，包括血液供应生长的肿瘤（血管生成）。几乎没有研究应力介质（例如去甲肾上腺素和肾上腺素）对血管生成的影响。血管内皮生长因子（VEGF）和白介素8（IL-8）是可以刺激肿瘤血管生成的关键因素。我们拥有引人注目的初步数据，即儿茶酚胺可以直接增加卵巢癌细胞的促血管生成细胞因子（例如VEGF和IL-8）的产生，并且可以通过使用β-肾上腺素能受体的抑制剂来阻止这种作用。该项目旨在检查与压力相关的介质（去甲肾上腺素，肾上腺素和皮质醇）对卵巢癌细胞促血管生成细胞因子分泌的影响，其对癌症进展的影响。我们设计了一系列实验，这些实验将确定应力介体可以实现这些影响的潜在机制和途径。我们还将确定应力介质对卵巢癌的生长和血管生成的体内影响，以及使用体内卵巢癌转移的体内原位小鼠模型阻止这些有害作用的特定方法的影响。这项研究的结果可能导致鉴定出加速卵巢癌生长的新机制，因此可能导致新的治疗方法。