Role of Src in Stress-Mediated Progression of Ovarian Cancer

卵巢癌在所有妇科恶性肿瘤中死亡率最高。因此，识别 加速癌症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， 在大多数晚期卵巢肿瘤中被激活。Src介导肿瘤的生物学功能， 肿瘤相关内皮细胞，并促进负责肿瘤进展的细胞间信号传导 和转移。此外，Src已被证明是肿瘤血管生成中的关键参与者，这是 主要通过激活导致VEGF、IL-8和IL-6分泌的途径来实现。的影响 先前已经描述了对癌症中免疫学参数的应激。然而，人们所知甚少， 关于压力因素影响癌症生长和发展的其他机制。应力 激活自主神经系统（ANS）和下丘脑-垂体-肾上腺（HPA）轴，通过 中枢神经系统ANS的激活导致从细胞中释放儿茶酚胺。 交感神经和肾上腺引起战斗或逃跑的应激反应，可能导致 促进血管生成，加速肿瘤生长和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。我提出一个假设 儿茶酚胺通过β-肾上腺素能受体介导激活 卵巢癌细胞中的Src。以下具体目标旨在检验这一假设。 具体目标1。确定儿茶酚胺诱导Src的机制和细胞后果 通过分析肿瘤细胞培养物中RNA/蛋白质表达谱的变化， 激动剂和拮抗剂。 具体目标2。为了确定Src激活加速肿瘤生长的需要， 使用生理学和药理学应激模型在体内环境中观察转移。 总之，这些实验将提供关于肿瘤中应力诱导的加速的重要见解。 生长以及这些有害影响的潜在机制。这些研究将提供更好的 了解生长因子受体酪氨酸激酶途径与β-肾上腺素能受体之间的相互作用 受体途径，并阐明它们的相互作用，导致卵巢癌生长的进展， 转移

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