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: 8834591
• 负责人: Patrick Louis Mulcrone
• 金额: $ 2.75万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834591
• 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; Disseminated Malignant Neoplasm; Distant; Emotional; Endothelial Cells; Endothelium; Engraftment; Etiology; Event; Extravasation; Gene Expression; Genetic; Goals; Human; IL6 gene; Immobilization; In Vitro; 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 Lesion; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Metatarsal bone structure; Mus; NF-kappa B; Neoplasm Metastasis; Nerve; Norepinephrine; Organ; Osteoblasts; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Property; Proteins; Psychosocial Stress; Receptor Signaling; Recurrence; Relapse; Role; Secondary Lesion; Signal Transduction; Site; Skeleton; Sorting - Cell Movement; Stimulus; Stress; Sympathetic Nervous System; TRANCE protein; Testing; Travel; Tumor Cell Line; VEGFA gene; Vascular Endothelial Growth Factors; Woman; angiogenesis; base; bone; bone stress; cancer cell; cancer diagnosis; cancer recurrence; cancer type; cell motility; cytokine; density; design; 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; research study; 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（由申请人提供）：癌症转移是一种罕见的生物学事件，但它是约80%的所有癌症死亡的原因。乳腺癌是女性中第二大致命癌症，经常转移到骨，骨是一个高度血管化并受交感神经系统（SNS）支配的器官。引起压力的情绪和心理刺激激活SNS，并与包括乳腺癌在内的多种癌症类型的患者生存期缩短和复发率增加有关。我们的实验室已经表明，SNS激活启动骨微环境，以有利于乳腺癌细胞的建立，并且NF-kB配体（RANKL）/RANK信号传导的受体激活剂通过促进乳腺癌细胞迁移有助于这一过程。此外，临床数据表明乳腺癌骨转移和骨髓血管生成增加之间存在相关性，表明血管机制可能起作用。由于循环系统是转移性肿瘤细胞定植于远处器官的主要通道，因此压力可能通过骨血管系统的改变促进乳腺癌转移。我的初步数据显示，SNS激活后成骨细胞中的VEGFA和IL 6表达水平增加。这些细胞因子以不同的方式影响内皮细胞，从而促进骨转移。因此，我们假设应力诱导的成骨细胞ADRB 2信号转导转化骨血管，以促进转移性乳腺癌外渗。在本提案的目标之一中，将在SNS激活下评估血管密度的变化。将测量血管数量和尺寸，以确定SNS激活是否改变骨血管布局。缺乏SNS激活成分的遗传小鼠模型以及不同的血管生成抑制剂的治疗将阐明血管密度在骨转移中的作用。应力如何影响肿瘤细胞与骨髓内皮细胞的粘附是目标二的重点。将通过选定粘附蛋白的基因表达、功能性体外试验以及功能丧失遗传小鼠模型来评估这些相互作用。