Stress, Sympathetic Activation and Breast Tumor Growth and Metastasis

压力、交感神经激活与乳腺肿瘤生长和转移

• 批准号: 7975853
• 负责人: KELLEY S MADDEN
• 金额: $ 23.29万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7975853
• 关键词: Ablation; Adrenergic Agonists; Adrenergic Receptor; Biochemical; Biological; Blood Vessels; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Cancer Patient; Cancer cell line; Cardiovascular Diseases; Catecholamines; Chronic; Chronic stress; Dextrans; Emotional Stress; Epinephrine; Fatty acid glycerol esters; Fibroblast Growth Factor 2; Gelatinase A; Gelatinase B; Goals; Growth; Hormones; Housing; Human; Image; Immunodeficient Mouse; Implant; Interleukin-6; Knowledge; Label; Laser Scanning Microscopy; Lead; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Mediator of activation protein; Molecular; Monitor; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Nerve; Nerve Fibers; Neurotoxins; Neurotransmitter Receptor; Norepinephrine; Oxidopamine; PECAM1 gene; Pathogenesis; Pathway interactions; Physiological; Recurrence; Role; Signal Transduction; Social isolation; Source; Stress; Sympathetic Nervous System; Testing; Therapeutic; Transgenic Mice; Tumor Angiogenesis; Tyrosine 3-Monooxygenase; Vascular Endothelial Growth Factors; Viral Tumor Antigens; Work; Xenograft procedure; angiogenesis; biological adaptation to stress; cancer therapy; density; dextran; enhanced green fluorescent protein; implantation; in vivo; insight; malignant breast neoplasm; mammary tumor virus; mouse model; nerve supply; neurotransmitter release; prevent; promoter; public health relevance; research study; rhodamine dextran; sialosyl-T antigen; stressor; tetramethylrhodamine; tumor; tumor growth; tumor progression

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.

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的生理损伤和随后的治疗。来自乳腺癌患者的证据表明，压力会促进乳腺肿瘤的生长和复发，但其生化机制尚不清楚。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受体，构成了小鼠和人类的主要应激途径。我们在小鼠乳腺脂肪垫中生长的乳腺肿瘤中观察到邻近血管的交感酪氨酸羟化酶阳性神经纤维。我们还确定，用 ss-肾上腺素能受体激动剂刺激乳腺癌细胞系可显着提高白细胞介素 6 (IL-6)，这是一种促进肿瘤血管生成、侵袭和转移的分子。在这个提议中，我们假设慢性压力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）和自发发生的小鼠乳腺癌模型（具体目标 2）中描述社会隔离（一种慢性压力源）对肿瘤生长和转移的影响。在这些实验中，我们将确定交感神经支配的消融或 ss-肾上腺素能受体的阻断是否可以防止应激诱导的肿瘤发病机制的改变。在具体目标 3 中，我们将描述体内交感神经支配与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）和多光子激光扫描显微镜（MPLSM）体内成像来动态监测肿瘤脉管系统（用四甲基罗丹明-葡聚糖（红色）标记）和 生长中的肿瘤中 EGFP 标记的 TH+ 神经纤维（绿色）。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治疗心血管疾病方面是安全有效的，这为其快速应用以改善当前乳腺癌治疗提供了可能性。 公共健康相关性：我们的研究将在两种乳腺癌小鼠模型中将压力暴露和压力激素去甲肾上腺素和肾上腺素与癌症生长和扩散联系起来。这项工作将立即深入了解长期压力暴露如何影响乳腺癌的生长和转移，并将为乳腺癌的治疗提供更多选择。