交感神经激活和 RANKL/IL6 在乳腺癌骨转移中的作用-猫眼课题宝

交感神经激活和 RANKL/IL6 在乳腺癌骨转移中的作用

批准号：

8502897

负责人：

Florent Elefteriou

金额：

$32.37万

依托单位：

VANDERBILT UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

2013

资助国家：

美国

项目状态：

已结题

起止时间：

2013-04-01 至 2018-03-31

来源：

https://reporter.nih.gov/project-details/8502897

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 Receptor Signaling 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

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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).

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