Role of Sympathetic Activation and RANKL/IL6 in Breast Cancer Bone Metastasis

交感神经激活和 RANKL/IL6 在乳腺癌骨转移中的作用

• 批准号: 8637019
• 负责人: Florent Elefteriou
• 金额: $ 31.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637019
• 关键词: Address; Adhesions; Adjuvant Therapy; Adrenergic Receptor; Affect; Binding; Biological Assay; Biopsy; Bone Marrow Cells; Bone Resorption; Bone neoplasms; Breast; Breast Cancer Cell; Breast Cancer Early Detection; Breast Carcinoma; Cancer Patient; Cancer cell line; Catecholamines; Cell Lineage; Cells; Cessation of life; Chronic; Chronic stress; Clinical; Data; Depressed mood; Detection; Disseminated Malignant Neoplasm; Distal; Distant; Event; Genetic; Goals; Homeostasis; IL6 gene; In Vitro; Injection of therapeutic agent; Laboratories; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Mental Depression; Metastatic Neoplasm to the Bone; Modeling; Molecular; Mus; Neoplasm Metastasis; Neurons; Nude Mice; Organ; Osteoblasts; Osteolysis; Pain; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Propranolol; Prostate carcinoma; Psychosocial Stress; Recurrence; Reporting; Research; Role; Series; Signal Transduction; Site; Solid; Specificity; Stromal Cells; Survival Rate; Sympathetic Nervous System; TNFSF11 gene; Testing; Time; Transgenes; Tumor Burden; Woman; Work; base; bone; cancer cell; cell motility; chronic depression; clinically relevant; cytokine; improved; in vitro Assay; in vivo; interest; knock-down; malignant breast neoplasm; mouse model; osteoclastogenesis; pre-clinical; prevent; programs; protective effect; psychosocial; public health relevance; receptor; receptor expression; response; restraint stress; tumor

DESCRIPTION (provided by applicant): Early detection of breast cancer and new treatments have now put the 5 year survival rate of patients above 99% and virtually all breast cancer deaths are the result of distal metastases, thus preventing metastasis and recurrence is of great clinical importance. The overall goal of this work is to address whether sympathetic nervous system (SNS) activation induced by chronic stress or depression in breast cancer patients contributes to bone metastasis, recurrence and survival. Clinical evidence and experimental data accumulated in our laboratory, using two mouse models of cancer metastasis to bone, support this hypothesis. Our data also point to osteoblast-derived cytokines RANKL and IL6 as a crucial factor promoting the colonization of cancer cells in the bone microenvironment in response to SNS activation, in addition to their effect on osteoclastogenesis and osteolysis. We propose in this application to characterize the cellular and molecular mechanisms underlying these SNS effects (Aim 1 and 2) and to address whether ?-blockers and RANKL blockade have beneficial effects on bone metastasis and survival in preclinical mouse models characterized by endogenous sympathetic activation (Aim 3).

描述（申请人提供）：乳腺癌的早期发现和新的治疗方法现已使患者的5年生存率超过99%，几乎所有乳腺癌死亡都是远端转移的结果，因此防止转移和复发具有重要的临床意义。这项工作的总体目标是解决乳腺癌患者慢性压力或抑郁引起的交感神经系统（SNS）激活是否有助于骨转移、复发和生存。我们实验室使用两种癌症骨转移小鼠模型积累的临床证据和实验数据支持了这一假设。我们的数据还表明，成骨细胞衍生的细胞因子 RANKL 和 IL6 除了对破骨细胞生成和骨溶解的影响外，也是响应 SNS 激活而促进骨微环境中癌细胞定植的关键因素。我们在本申请中建议表征这些 SNS 效应背后的细胞和分子机制（目标 1 和 2），并探讨 β-阻滞剂和 RANKL 阻断是否对以内源性交感神经激活为特征的临床前小鼠模型中的骨转移和存活产生有益影响（目标 3）。