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: 7546613
• 负责人: GUILLERMO N ARMAIZ-PENA
• 金额: $ 2.7万
• 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/7546613
• 关键词: Acceleration; Activation Analysis; Address; Adrenal Glands; Adrenergic Receptor; Affect; Agonist; Autonomic nervous system; Biological Process; Cancer Patient; Catecholamines; Cell Line; Chronic; Cultured Tumor Cells; Data; Development; Endothelial Cells; Growth; Growth Factor; Gynecologic; Hormones; Hypothalamic structure; IL8 gene; In Vitro; Interleukin-6; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular Profiling; Neoplasm Metastasis; Nerve; Neuraxis; Nude Mice; Outcome; Ovarian Carcinoma; Pathway interactions; Physiological; Pituitary Gland; Play; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Signal Transduction; Staging; Stress; Testing; Tumor Angiogenesis; Vascular Endothelial Growth Factors; angiogenesis; biological adaptation to stress; cancer cell; design; fighting; hypothalamic-pituitary-adrenal axis; in vivo; insight; migration; mortality; new therapeutic target; ovarian neoplasm; protein expression; research study; restraint stress; tumor; tumor growth; tumor progression

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 P-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 p-adrenergic receptor pathway and elucidate their interactions that result in progression of ovarian cancer growth and metastases

卵巢癌是所有妇科恶性肿瘤中死亡率最高的。因此，身份识别 导致癌症加速生长的因素至关重要，并可能导致 开发新的治疗靶点。SRC是一种非受体酪氨酸激酶，过度表达和 在大多数晚期卵巢肿瘤中被激活。SRC介导肿瘤和肿瘤的生物学功能 肿瘤相关内皮细胞，并促进负责肿瘤进展的细胞间信号转导 和转移。此外，Src已被证明在肿瘤血管生成中起关键作用，这是 主要通过激活导致分泌血管内皮生长因子、白介素8和白介素6的通路来实现。的影响 对癌症免疫参数的压力已在以前被描述过。然而，人们对此知之甚少， 关于压力因素影响癌症生长和进展的其他机制。压力 激活自主神经系统(ANS)和下丘脑-垂体-肾上腺(HPA)轴 中枢神经系统。激活ANS导致儿茶酚胺从 交感神经和肾上腺引起战斗或逃跑的应激反应，这可能导致 促进血管生成，加速肿瘤生长，促进肿瘤细胞侵袭和迁移。 然而，这些观察结果背后的机制还没有完全被理解。我提出了这个假设 儿茶酚胺通过P-肾上腺素能受体介导的活化促进肿瘤生长和进展 卵巢癌细胞中的SRC。为了检验这一假设，我们设计了以下具体目标。 具体目的1.确定儿茶酚胺诱导的自发性高血压的机制和细胞后果 通过分析肿瘤细胞培养物中特异性RNA/蛋白质表达谱的变化来激活 激动剂和拮抗剂。 具体目标2.确定加速肿瘤生长所需的Src激活和 使用生理和药物应激模型的活体环境中的转移。 总而言之，这些实验将提供关于应力诱导的肿瘤加速的重要见解。 增长和这些有害影响背后的机制。这些研究将提供更好的 生长因子受体酪氨酸激酶通路与β-肾上腺素能信号通路的相互作用 受体途径并阐明它们之间的相互作用导致卵巢癌的生长和进展 转移瘤