Role of Src in Stress-Mediated Progression of Ovarian Cancer

Src 在压力介导的卵巢癌进展中的作用

• 批准号: 7229765
• 负责人: GUILLERMO N ARMAIZ-PENA
• 金额: $ 4.24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-11-16 至 2009-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229765
• 关键词: catecholamines; lead; metastasis; neoplasm /cancer; neoplastic growth; ovary neoplasms; role; stress

DESCRIPTION (provided by applicant): Ovarian cancer has the highest mortality rate among all gynecologic malignancies. Therefore, identification of factors responsible for its accelerated cancer growth is of critical importance and may lead to development of novel therapeutic targets. Src, a non-receptor tyrosine kinase, is over-expressed and activated in a majority of late-stage ovarian tumors. Src mediates biological functioning of both tumor and tumor-associated endothelial cells, and promotes intercellular signaling responsible for tumor progression and metastasis. In addition, Src has proven to be a critical player in tumor angiogenesis and this is achieved mainly by activating pathways that lead to the secretion of VEGF, IL-8 and IL-6. The effect of stress on immunological parameters in cancer has been previously described. Little is known, however, about other mechanisms by which stress factors can affect the growth and progression of cancer. Stress activates the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis via the central nervous system. Activation of the ANS results in the release of catecholamines from the sympathetic nerves and adrenal glands causing a fight-or-flight stress response that may lead to the promotion of angiogenesis, acceleration of tumor growth and the invasion and migration of tumor cells. However, the mechanisms underlying these observations are not fully understood. I propose the hypothesis that catecholamines promote tumor growth and progression by beta-adrenergic receptor mediated activation of Src in ovarian cancer cells. The following specific aims are designed to test this hypothesis. Specific Aim 1. To determine the mechanisms and cellular consequences of catecholamine-induced Src activation by analyzing changes in RNA/Protein expression profile of tumor cell cultures with specific agonists and antagonists. Specific Aim 2. To determine the requirement for Src activation for acceleration of tumor growth and metastasis in an in vivo setting using physiological and pharmacological stress models. Together, these experiments will provide important insights regarding stress-induced acceleration in tumor growth and the mechanisms underlying these deleterious effects. These studies will provide a better understanding of the crosstalk between growth factor receptor tyrosine kinase pathway and beta-adrenergic receptor pathway and elucidate their interactions that result in progression of ovarian cancer growth and metastases.

描述（由申请人提供）：卵巢癌在所有妇科恶性肿瘤中死亡率最高。因此，确定其加速癌症生长的因素至关重要，并可能导致新的治疗靶点的开发。Src是一种非受体酪氨酸激酶，在大多数晚期卵巢肿瘤中过度表达和激活。Src介导肿瘤和肿瘤相关内皮细胞的生物学功能，并促进负责肿瘤进展和转移的细胞间信号传导。此外，Src已被证明是肿瘤血管生成的关键参与者，这主要是通过激活导致VEGF、IL-8和IL-6分泌的途径来实现的。先前已经描述了应激对癌症中免疫学参数的影响。然而，人们对压力因素影响癌症生长和进展的其他机制知之甚少。应激通过中枢神经系统激活自主神经系统（ANS）和下丘脑-垂体-肾上腺（HPA）轴。ANS的激活导致从交感神经和肾上腺释放儿茶酚胺，引起战斗或逃跑应激反应，这可能导致促进血管生成、加速肿瘤生长以及肿瘤细胞的侵袭和迁移。然而，这些观察结果背后的机制尚未完全了解。我提出的假设是，儿茶酚胺促进肿瘤的生长和进展，β-肾上腺素能受体介导的激活Src在卵巢癌细胞。以下具体目标旨在检验这一假设。具体目标1.通过分析使用特定激动剂和拮抗剂的肿瘤细胞培养物的RNA/蛋白质表达谱的变化，确定儿茶酚胺诱导Src激活的机制和细胞后果。具体目标2。使用生理学和药理学应激模型确定体内环境中Src激活加速肿瘤生长和转移的需求。总之，这些实验将提供有关应力诱导的肿瘤生长加速和这些有害影响的机制的重要见解。这些研究将提供一个更好的理解之间的串扰生长因子受体酪氨酸激酶途径和β-肾上腺素能受体途径，并阐明它们的相互作用，导致卵巢癌的生长和转移的进展。