Effect of skeletal compression on tumor growth and migration

骨骼压缩对肿瘤生长和迁移的影响

• 批准号: 9889087
• 负责人: Hiroki Yokota
• 金额: $ 7.88万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889087
• 关键词: 3-Dimensional; 4T1; Address; Affect; Affinity; Benefits and Risks; Biological Assay; Bone Matrix; Bone neoplasms; Breast Cancer Cell; Breast Cancer cell line; Breast cancer metastasis; Cancer Center; Cancer Relapse; Cell Culture Techniques; Cells; Conditioned Culture Media; Data; Development; Doctor of Philosophy; Elderly; Fibronectins; Gene Expression; Genes; Goals; Growth Factor; Guidelines; Heat shock proteins; Heat-Shock Proteins 90; Histology; Human; In Vitro; Indiana; Injections; Invaded; Jogging; Label; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mass Spectrum Analysis; Mechanical Stimulation; Mechanics; Metastatic Neoplasm to the Bone; Molecular; Molecular Target; Neoplasm Metastasis; Osteocytes; Osteogenesis; Outcome; Physical activity; Physical therapy; Regulation; Risk; Roentgen Rays; Role; Shear Strength; Site; Snails; Stress; Techniques; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transitional Cell Neoplasm; Tumor Cell Invasion; Tumor Cell Migration; Universities; Walking; Weight-Bearing state; Woman; bone; bone cell; bone loss; cancer risk; carcinogenesis; cell motility; cell type; differential expression; epithelial to mesenchymal transition; fluid flow; fluorescence imaging; malignant breast neoplasm; mechanotransduction; microCT; migration; monolayer; mouse model; neoplastic cell; nucleolin; prevent; response; risk benefit ratio; shear stress; skeletal; tibia; tumor; tumor growth

PROJECT SUMMARY The long-term objective of this NCI R03 project (Effect of skeletal compression on tumor growth and migration) is to contribute to developing guidelines for physical therapies that most effectively reduce the risk of cancer induction and relapse. The specific goal of this project is to evaluate the role of skeletal compression (bone loading) in regulating tumor growth and epithelial-to-mesenchymal transition (EMT) in the bone microenvironment. Focusing on bone metastasis associated with breast cancer, we will evaluate interactions of tumor cells with osteocytes, the most abundant type of cells in bone matrix, in the presence and absence of mechanical stimulation. One out of eight women suffers breast cancer in her lifetime, and bone is one of the most frequent sites of metastasis. Currently, we know little about the impact of osteocyte-driven mechanotransduction in tumor-bone interactions and bone metastasis. Preliminary studies suggest that osteocytes act as an attractant of tumor cells, but application of fluid flow shear stress reverses the attraction and leads to EMT. An intriguing question is whether mechanical stimulation to osteocytes may act as a regulatory switch of tumor EMT. Our working hypothesis is: Mechanical stimulation inhibits proliferation and stimulates migration of tumor cells in the loaded bone by regulating Src in tumor-osteocyte interactions. To test this hypothesis, we will conduct two specific aims: Aim 1: Evaluate the effect of skeletal compression in tumor growth and invasion using a mouse model. Aim 2: Determine the mechanism of action of mechanical stimulation in tumor-osteocyte interactions. In Aim 1, we will use a mouse model of skeletal loading to determine tumor growth and migration associated with breast cancer (mammary tumor) in the bone microenvironment. In Aim 2, we will employ monolayer cell cultures and 3D spheroids to evaluate tumor-osteocyte interactions in the presence and absence of oscillatory fluid flow shear stress. We will focus on genes involved in EMT and mechanotransduction of bone such as TGFβ and Src, as well as mechano-sensitive factors (e.g., fibronectin, heat shock protein, nucleolin) that were identified by mass spectrometry in osteocyte-derived conditioned mediums. We expect that this project will contribute to a basic understanding of the role of skeletal compression in tumor growth and invasion in the bone microenvironment. We also expect that the results will contribute to the provision of risk-benefit analysis of loading-linked physical activities, such as walking and jogging, as well as the establishment of a therapeutic guideline for bone metastasis.

项目总结 NCI R03项目的长期目标(骨骼压缩对肿瘤生长和 移民)是帮助制定物理治疗指南，最有效地降低癌症风险 癌症的诱发和复发。这个项目的具体目标是评估骨骼压缩的作用。 (骨负荷)在调节骨肿瘤生长和上皮间充质转化(EMT)中的作用 微环境。聚焦于与乳腺癌相关的骨转移，我们将评估 肿瘤细胞与骨细胞，骨基质中最丰富的细胞类型，在存在和不存在 机械刺激。每八名女性中就有一名在一生中患有乳腺癌，而骨骼是 最常见的转移部位。目前，我们对骨细胞驱动的影响知之甚少 肿瘤-骨相互作用和骨转移中的力学转导。初步研究表明， 骨细胞作为肿瘤细胞的引诱剂，但应用流体流动剪应力可以逆转这种吸引。 并导致急诊抢救。一个耐人寻味的问题是，对骨细胞的机械刺激是否可能起到 肿瘤EMT的调节开关。我们的工作假设是：机械刺激抑制增殖和 通过调节肿瘤-骨细胞相互作用中的Src来刺激肿瘤细胞在负荷骨中的迁移。为了测试 在这个假设中，我们将进行两个具体的目标： 目的1：用小鼠模型评价骨骼压迫对肿瘤生长和侵袭的影响。 目的2：探讨机械刺激在肿瘤-骨细胞相互作用中的作用机制。 在目标1中，我们将使用骨骼负荷的小鼠模型来确定与肿瘤生长和迁移相关的 伴有乳腺癌(乳腺肿瘤)的骨骼微环境。在目标2中，我们将使用单层细胞 培养和3D球体在有无振荡的情况下评估肿瘤-骨细胞的相互作用 流体流动剪应力。我们将重点研究与骨的EMT和机械转导有关的基因，如转化生长因子β 以及已鉴定的机械敏感因子(如纤维连接蛋白、热休克蛋白、核仁素)。 通过在骨细胞来源的条件培养液中进行质谱分析。我们希望这个项目将有助于 对骨骼受压在骨肿瘤生长和侵袭中作用的基本认识 微环境。我们还预计，结果将有助于提供风险-收益分析 与负荷相关的体力活动，如散步和慢跑，以及建立治疗性 骨转移指南。

项目成果

Generation of the tumor-suppressive secretome from tumor cells.

从肿瘤细胞中产生肿瘤抑制性分泌组。

• DOI: 10.7150/thno.61006
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Liu S;Sun X;Li K;Zha R;Feng Y;Sano T;Dong C;Liu Y;Aryal UK;Sudo A;Li BY;Yokota H
• 通讯作者: Yokota H