Influence of Stress on Bone Vasculature and Bone Metastasis

 描述(申请人提供)：癌症转移是一种罕见的生物学事件，但它是导致所有癌症死亡的大约80%。乳腺癌是女性第二致命的癌症，通常会转移到骨骼，这是一个高度血管化的器官，由交感神经系统(SNS)神经支配。引起压力的情绪和心理社会刺激激活了SNs，并与包括乳腺癌在内的多种癌症类型的患者较短的生存期和增加复发率有关。我们的实验室已经证明，SNS的激活启动了有利于乳腺癌细胞建立的骨骼微环境，而核因子-kB配体受体激活剂(RANKL)/RANK信号通路通过促进乳腺癌细胞的迁移而参与了这一过程。此外，临床数据表明乳腺癌骨转移与骨髓血管生成增加之间存在相关性，提示血管机制可能起作用。由于循环系统是转移的肿瘤细胞定植到远处器官的主要通道，应激可能通过改变骨血管来促进乳腺癌的转移。我的初步数据显示，在SNS激活后，成骨细胞中VEGFA和IL6的表达水平增加。这些细胞因子以不同的方式影响内皮细胞，可能促进骨转移。因此，我们假设应激诱导的成骨细胞ADRB2信号改变骨血管以促进转移性乳腺癌的渗出。其中一项建议是在SNS激活下对血管密度的变化进行评估。将测量血管的数量和大小，以确定SNS激活是否改变了骨血管的布局。缺乏SNS激活成分的遗传性小鼠模型以及治疗将不同的血管生成抑制剂将阐明血管密度在骨转移中的作用。应激如何影响肿瘤细胞与骨髓内皮细胞的黏附是目标二的焦点。这些相互作用将通过选定的黏附蛋白的基因表达、体外功能测试以及功能丧失的小鼠遗传模型来评估。

 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.