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.

项目摘要 该NCI R03项目的长期目标（骨骼压缩对肿瘤生长和 迁移）是为制定物理疗法指南做出贡献，这些准则最有效地降低了 癌症诱导和复发。该项目的具体目标是评估骨骼压缩的作用 （骨负荷）调节肿瘤生长和上皮到间质转变（EMT）的（EMT） 微环境。专注于与乳腺癌相关的骨转移，我们将评估 肿瘤细胞具有骨细胞，骨基质中最丰富的细胞类型，在存在和不存在的情况下 机械刺激。八分之一的妇女一生都患乳腺癌，而骨头是其中之一 最常见的转移部位。目前，我们对骨细胞驱动的影响一无所知 肿瘤骨相互作用和骨转移的机械转导。初步研究表明 骨细胞充当肿瘤细胞的吸引力，但是流体流动剪应力的应用会逆转吸引力 并导致EMT。一个有趣的问题是对骨细胞的机械刺激是否可以充当 肿瘤EMT的调节转换。我们的工作假设是：机械模拟抑制了增殖和 通过调节肿瘤 - 骨细胞相互作用中的SRC来刺激肿瘤细胞的迁移。测试 这个假设，我们将进行两个具体的目的： AIM 1：使用小鼠模型评估骨骼压缩在肿瘤生长和侵袭中的影响。 AIM 2：确定机械刺激在肿瘤骨相互作用中的作用机理。 在AIM 1中，我们将使用骨骼负荷的小鼠模型来确定肿瘤的生长和迁移 骨微环境中的乳腺癌（乳腺肿瘤）。在AIM 2中，我们将使用单层单元格 在存在和不存在振荡的情况下，培养物和3D球体评估肿瘤 - 骨细胞相互作用 流体流动剪应力。我们将专注于涉及EMT和骨骼的机械转导的基因，例如TGFβ 和SRC以及机械敏感因子（例如，纤连蛋白，热激蛋白，核素）被鉴定出来 通过骨细胞衍生的条件培养基中的质谱法。我们希望这个项目将有助于 对骨骼压缩在肿瘤生长中的作用的基本理解 微环境。我们还期望结果将有助于提供风险效益分析 加载连锁的体育活动，例如步行和慢跑，以及建立疗法 骨转移指南。

项目成果

Generation of the tumor-suppressive secretome from tumor cells.

• 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