Stress, Sympathetic Activation and Breast Tumor Growth and Metastasis

描述（由申请人提供）：在乳腺癌患者中，慢性情绪压力伴随着癌症和后续治疗的生理损害。有证据表明，乳腺癌患者的压力可以增加乳腺肿瘤的生长和复发，但生化机制尚不清楚。交感神经系统释放儿茶酚胺、去甲肾上腺素和肾上腺素以及激活肾上腺素能受体构成了小鼠和人类的主要应激途径。我们观察到交感神经酪氨酸羟化酶阳性神经纤维邻近血管的乳腺肿瘤生长在乳腺脂肪垫的小鼠。我们还确定，β-肾上腺素能受体激动剂刺激乳腺癌细胞系显着提高白细胞介素-6（IL-6），一种促进肿瘤血管生成，侵袭和转移的分子。在这个提议中，我们假设慢性应激暴露通过激活交感神经系统刺激肿瘤生长、血管生成和转移。我们将在小鼠原位乳腺癌模型（具体目标1）和自发发生的乳腺癌小鼠模型（具体目标2）中描述社会隔离（一种慢性应激源）对肿瘤生长和转移的影响。在这些实验中，我们将确定是否消融交感神经支配或阻断β-肾上腺素能受体可以预防肿瘤发病机制中的应激诱导的改变。在具体目标3中，我们将在体内描述交感神经支配和肿瘤血管之间的解剖关系。我们将使用在酪氨酸羟化酶启动子控制下表达增强型绿色荧光蛋白（EGFP）的转基因小鼠（TH-EGFP小鼠），并使用多光子激光扫描显微镜（MPLSM）进行体内成像，以动态监测生长肿瘤中肿瘤血管系统（用四甲基罗丹明-葡聚糖（红色）标记）和EGFP标记的TH+神经纤维（绿色）之间的关系。这些实验将确定交感神经系统在应激诱导的肿瘤进展中的作用。交感神经系统的药理学阻断剂已被证明在心血管疾病的治疗中是安全有效的，为它们的快速应用提供了可能性，以改善当前的乳腺癌治疗。 公共卫生相关性：我们的研究将把压力暴露和压力激素去甲肾上腺素和肾上腺素与两种乳腺癌小鼠模型中的癌症生长和扩散联系起来。这项工作将为长期压力暴露如何影响乳腺癌的生长和转移提供直接的见解，并将为乳腺癌的治疗提供更多的选择。

DESCRIPTION (provided by applicant): In breast cancer patients, chronic emotional stress accompanies the physiological toll of the cancer and subsequent therapeutic treatment. There is evidence from breast cancer patients that stress can augment breast tumor growth and recurrence, but the biochemical mechanisms are not understood. Sympathetic nervous system release of the catecholamines norepinephrine and epinephrine and activation of adrenergic receptors constitute a major stress pathway in mice and humans. We have observed sympathetic tyrosine hydroxylase-positive nerve fibers adjacent to blood vessels in breast tumors grown in the mammary fat pad of mice. We have also determined that stimulation of breast cancer cell lines with ss-adrenergic receptor agonists dramatically elevates interleukin-6 (IL-6), a molecule that facilitates tumor angiogenesis, invasion and metastasis. In this proposal, we hypothesize that chronic stress exposure stimulates tumor growth, angiogenesis, and metastasis through activation of the sympathetic nervous system. We will characterize the impact of social isolation, a chronic stressor, on tumor growth and metastasis in a mouse orthotopic breast cancer model (specific aim 1) and in a spontaneously occurring mouse model of breast cancer (specific aim 2). In these experiments, we will determine if ablation of sympathetic innervation or blockade of ss-adrenergic receptors prevent stress-induced alterations in tumor pathogenesis. In specific aim 3, we will characterize the anatomical relationship between sympathetic innervation and tumor blood vessels in vivo. We will use transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase promoter (TH-EGFP mice) and in vivo imaging with multiphoton laser scanning microscopy (MPLSM) to dynamically monitor the relationship between the tumor vasculature (labeled with tetramethyl rhodamine-dextran (red)) and EGFP-labeled TH+ nerve fibers (green) in a growing tumor. These experiments will define the role of the sympathetic nervous system in stress-induced tumor progression. Pharmacological blockers of the sympathetic nervous system have been proven safe and effective in the treatment of cardiovascular disease, offering the possibility of their rapid application to the improvement of current breast cancer therapies. PUBLIC HEALTH RELEVANCE: Our studies will connect stress exposure and the stress hormones norepinephrine and epinephrine to cancer growth and spread in two mouse models of breast cancer. This work will provide immediate insight into how long-term stress exposure influences breast cancer growth and metastasis, and will lead to additional options for the treatment of breast cancer.