Role of Src in Stress-Mediated Progression of Ovarian Cancer

描述（由申请人提供）：卵巢癌是所有妇科恶性肿瘤中死亡率最高的。因此，确定导致其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已被证明在肿瘤血管生成中起关键作用，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。应激对癌症中免疫参数的影响先前已被描述过。然而，人们对压力因素影响癌症生长和发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-肾上腺轴（HPA）。ANS的激活导致交感神经和肾上腺释放儿茶酚胺，引起“战或逃”应激反应，从而促进血管生成，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不完全清楚。我提出了一种假说，即儿茶酚胺通过β -肾上腺素能受体介导的卵巢癌细胞Src的激活促进肿瘤的生长和进展。以下具体目标旨在验证这一假设。具体目标通过分析使用特异性激动剂和拮抗剂的肿瘤细胞培养物中RNA/蛋白表达谱的变化，确定儿茶酚胺诱导Src活化的机制和细胞后果。具体目标2。利用生理和药理学应激模型，在体内环境下确定Src激活加速肿瘤生长和转移的必要性。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。这些研究将更好地理解生长因子受体酪氨酸激酶途径和β -肾上腺素能受体途径之间的串扰，并阐明它们之间的相互作用导致卵巢癌生长和转移的进展。

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.