Influence of Stress on Bone Vasculature and Bone Metastasis

应力对骨血管系统和骨转移的影响

• 批准号: 9197623
• 负责人: Patrick Louis Mulcrone
• 金额: $ 1.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197623
• 关键词: 4T1; ADRB2 gene; Address; Adhesions; Adrenergic Receptor; Affect; Agonist; Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiogenic Factor; Area; Avastin; Biological; Biological Assay; Blood Vessels; Bone Marrow; Breast Cancer Cell; Breast cancer metastasis; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Cessation of life; Chronic; Chronic stress; Clinical; Clinical Data; Coculture Techniques; Complement; Conditioned Culture Media; Data; Dextrans; Diffuse; Disease; Distant; Emotional; Endothelial Cells; Endothelium; Engraftment; Etiology; Event; Extravasation; Gene Expression; Genetic; Goals; Human; IL6 gene; Immobilization; In Vitro; Inbred BALB C Mice; Incidence; Infiltration; Injection of therapeutic agent; Isoproterenol; Laboratories; Lead; Lesion; Ligands; Limb structure; Link; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Measures; Mental Depression; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Metastatic to; Metatarsal bone structure; Mus; NF-kappa B; Neoplasm Metastasis; Nerve; Norepinephrine; Organ; Osteoblasts; Pathway interactions; Patients; Play; Process; Property; Proteins; Psychosocial Stress; Receptor Activation; Receptor Signaling; Recurrence; Relapse; Role; Secondary Lesion; Signal Transduction; Site; Skeleton; Stimulus; Stress; Sympathetic Nervous System; TRANCE protein; Testing; Travel; Tumor Cell Line; VEGFA gene; Vascular Endothelial Growth Factors; Woman; angiogenesis; base; bone; cancer cell; cancer diagnosis; cancer recurrence; cancer type; cell motility; cytokine; density; design; experimental study; in vitro Assay; in vivo; loss of function; malignant breast neoplasm; mouse model; neoplastic cell; outcome forecast; palliative; pre-clinical; psychosocial; public health relevance; receptor; targeted cancer therapy; tumor

 DESCRIPTION (provided by applicant): Cancer metastasis is a rare biological event, yet it is responsible for approximately 80% of all cancer deaths. Breast cancer, the second deadliest cancer among women, often metastasizes to bone, an organ that is highly vascularized and innervated by the sympathetic nervous system (SNS). Emotional and psychosocial stimuli that cause stress activate the SNS and are linked to shorter patient survival and increased recurrence in multiple cancer types including breast cancer. Our laboratory has shown that SNS activation primes the bone microenvironment to favor breast cancer cell establishment, and that receptor activator of NF-kB ligand (RANKL)/RANK signaling contributes to this process by promoting breast cancer cell migration. Furthermore, clinical data indicates a correlation between breast cancer bone metastases and increase bone marrow angiogenesis, suggesting a vascular mechanism might contribute. Because the circulatory system is the major conduit through which metastatic tumor cells colonization distant organs, stress may promote breast cancer metastasis via alterations in the bone vasculature. My preliminary data revealed that VEGFA and IL6 expression levels in osteoblasts are increased following SNS activation. These cytokines affect endothelial cells in distinct ways that could promote bone metastasis. We thus hypothesize that stress-induced osteoblastic ADRB2 signaling transmutes bone vasculature to facilitate extravasation of metastatic breast cancer. In aim one of this proposal, changes in vascular density will be assessed under SNS activation. Vessel number and size will be measured in order to determine whether SNS activation transforms the layout of bone vasculature. Genetic mouse models lacking components of SNS activation as well as treatments will different inhibitors of angiogenesis will elucidate the role of vessel density in bone metastases. How stress affects tumor cell adhesion to bone marrow endothelial cells is the focus of aim two. These interactions will be assessed through gene expression of selected adhesion proteins, functional in vitro assays, as well as through loss of function genetic mouse models.

 描述（由适用提供）：癌症转移是罕见的生物学事件，但造成了所有癌症死亡的约80％。乳腺癌是女性中第二个致命的癌症，经常转移到骨骼，这是一种高度血管和由交感神经系统（SNS）支配的器官。引起压力的情绪和社会心理刺激会激活SNS，并与患者较短的生存期和包括乳腺癌在内的多种癌症类型的复发增加有关。我们的实验室表明，SNS激活量骨微环境有利于乳腺癌细胞的建立，而NF-KB配体（RANKL）/等级信号的受体激活剂通过促进乳腺癌细胞迁移来促进这一过程。此外，临床数据表明乳腺癌骨转移与增加骨髓血管生成之间存在相关性，这表明血管机制可能有助于。由于电路系统是转移性肿瘤细胞定植远处器官的主要导管，因此应力可以通过骨管脉管系统的改变来促进乳腺癌转移。我的初步数据表明，在SNS激活后，成骨细胞中的VEGFA和IL6表达水平增加。这些细胞因子以可能促进骨转移的不同方式影响内皮细胞。因此，我们假设应激诱导的成骨细胞ADRB2信号传导会透射骨血管，以促进转移性乳腺癌的渗出。在此提案之一中，血管密度的变化将在SNS激活下评估。将测量容器的数量和大小，以确定SNS激活是否会改变骨血管的布局。缺乏SNS激活成分以及处理的遗传小鼠模型将使血管生成的不同抑制剂阐明血管密度在骨转移中的作用。应力如何影响肿瘤细胞对骨髓内皮细胞的粘附是目标二的重点。这些相互作用将通过选定的粘合蛋白，功能性评估以及功能遗传小鼠模型的丧失来评估。