Developing the coral implant model of bone metastasis

开发骨转移的珊瑚植入模型

• 批准号: 6686217
• 负责人: LYNN M MATRISIAN
• 金额: $ 15.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-17 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686217
• 关键词: bioengineering /biomedical engineering; biomaterial development /preparation; bone development; bone neoplasms; breast neoplasms; cell migration; coral; hydroxyapatites; immunocytochemistry; implant; in situ hybridization; laboratory mouse; metalloendopeptidases; metastasis; model design /development; neoplastic cell; osteocytes; tissue engineering; tissue support frame

DESCRIPTION (provided by applicant): Metastasis to the bone represents a significant clinical problem for patients with advanced stage breast cancer. The development of targeted therapies for the treatment and control of bone metastasis is hindered by the paucity of preclinical models that would allow the identification of the molecular mechanisms by which tumor cells are attracted and thrive in the bone microenvironment. The goal of this proposal is to develop a novel animal model to study the processes of extravasation and progression of metastatic bone disease using an in vivo generated 'vitalized' bone matrix. These studies represent a collaboration between cancer biologists with expertise in metastasis from a cellular and molecular perspective, and orthopedic surgeons with expertise in a novel tissue engineered model of skeletogenesis. Bone is generated in vivo by ligating a hydroxyapatite-substituted marine coral scaffold to a vascular leash or pedicle. The graft becomes populated with circulating bone progenitor cells, and bone osteoid can develop within 5 weeks. We propose to use this 'vitalized' bone to assess homing and progression of murine tumor cells following injection into the pedicle. The tumor cells will be tagged with the luciferase gene to allow visualization and monitoring with time using bioluminescent imaging techniques. This approach provides several advantages over existing methodology, including the limited dissemination of the tumor cells, the quantitative assessment of metastatic cell burden, and the ability to manipulate individual components of the bone microenvironment. In proof of principle experiments, we will use this methodology to address the hypothesis that production of the matrix metalloproteinases MMP-2 and MMP-9 by resident bone cells contributes to the ability of malignant breast cells to colonize and grow in the bone microenvironment. These studies will lay the foundation for further studies to identify novel targets for the treatment and control of breast-to-bone metastasis.

描述（由申请人提供）： 对于晚期乳腺癌患者来说，骨转移是一个重要的临床问题。由于缺乏临床前模型，无法识别肿瘤细胞在骨微环境中被吸引和生长的分子机制，因此阻碍了治疗和控制骨转移的靶向疗法的发展。该提案的目标是开发一种新型动物模型，利用体内生成的“活化”骨基质来研究转移性骨病的外渗和进展过程。这些研究代表了具有细胞和分子角度转移专业知识的癌症生物学家与具有新型骨骼发生组织工程模型专业知识的骨科医生之间的合作。通过将羟基磷灰石取代的海洋珊瑚支架与血管带或蒂结扎，在体内生成骨骼。移植物中充满了循环骨祖细胞，骨样骨可在 5 周内发育。我们建议使用这种“活化”的骨骼来评估注射到椎弓根后小鼠肿瘤细胞的归巢和进展。肿瘤细胞将被荧光素酶基因标记，以便使用生物发光成像技术随时间可视化和监测。与现有方法相比，这种方法具有多个优点，包括肿瘤细胞的有限传播、转移细胞负荷的定量评估以及操纵骨微环境的各个成分的能力。在原理实验证明中，我们将使用这种方法来解决以下假设：常驻骨细胞产生的基质金属蛋白酶 MMP-2 和 MMP-9 有助于恶性乳腺细胞在骨微环境中定殖和生长的能力。这些研究将为进一步研究奠定基础，以确定治疗和控制乳腺骨转移的新靶点。