Role of Perivascular Mesenchymal Stem Cells (pMSCs) in the Bone Marrow Niche and the Extracellular Matrix in the Control of Skeletal Metastasis

骨髓微环境中血管周围间充质干细胞 (pMSC) 和细胞外基质在控制骨骼转移中的作用

• 批准号: 10413249
• 负责人: Arnold Irwin Caplan
• 金额: $ 40.85万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413249
• 关键词: Address; Attenuated; Automobile Driving; Back; Basement membrane; Binding; Blood; Blood Vessels; Bone Marrow; Breast; Breast Cancer Cell; Breast Cancer cell line; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cancer Control; Cell Line; Cell Surface Receptors; Cells; Ceramics; Clinical; Communication; Cytoskeleton; Data; Databases; Diagnostic; Discontinuous Capillary; Disseminated Malignant Neoplasm; Engraftment; Extracellular Matrix; Extravasation; Future; Gatekeeping; Genes; Genetic; Genetic Models; Genetic Variation; Habitats; Hematopoietic; Hematopoietic stem cells; Homing; Human; Immune; Implant; Integrin alpha6beta1; Invaded; Laminin; Ligands; Location; MCAM gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Marrow; Melanins; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Modeling; Modification; Molecular; Molecular Target; Mus; Nature; Neoplasm Metastasis; Organ; Outcome; Patients; Pericytes; Platelet-Derived Growth Factor; Play; Population; Process; Production; Prostate; Protein Isoforms; Proto-Oncogene Protein c-kit; Regulation; Research Proposals; Role; Side; Site; Skeleton; Stem Cell Factor; Stream; Stromal Cell-Derived Factor 1; Supporting Cell; System; Testing; Therapeutic; Time; Tumor Angiogenesis; Tumor Cell Invasion; Work; anti-tumor immune response; base; bone; calcium phosphate; cancer cell; cell type; circulating cancer cell; clinically relevant; design; genetic variant; hematopoietic stem cell niche; improved; in vitro Assay; in vivo; innovation; melanoma; metastatic process; neoplastic cell; novel; patient response; prevent; substantia spongiosa; targeted treatment; trafficking; tumor; vascular factor

TECHNICAL ABSTRACT The skeleton is a preferred organ for cancer dissemination from various tumors malignancies. The main objective of this research proposal is to understand the function of the Bone Marrow microenvironment, and specifically of its perivascular components, in the establishment of skeletal metastasis. The studies that are proposed aim to test the innovative hypothesis that Mesenchymal Stem Cells (MSCs), as perivascular cells (pMSCs), function as gatekeepers controlling tumor cell invasion to the bone. This new hypothesis provides clinically relevant information for therapeutic strategies that innovately aim at reducing the engraftment of circulating cancer cells by closing the gate through which the metastatic cell transit into the normal bone. We propose that the inhibition of one or combination of tumor cells and pMSCs specific genes would prevent or attenuate the metastatic process in vivo. To experimentally dissect the various cellular and extracellular matrix components controlling extravasation, we have designed and validated a unique in vivo extraskeletal humanized bone marrow niche-mimicking platform (humanized Ossicle). This platform is centered around the use of a porous, calcium phosphate ceramic into which human bone marrow-derived MSCs (hBM-MSC) are loaded and then implanted into the back of immune deficient mice. Bone is fabricated onto the walls of the ceramic by hBM-MSCs anchored at these locations and, at the centers; the host-derived blood vessels have pMSCs within the marrow space. We have documented that when melanoma is injected into the blood stream of the mouse, the bones become black (melanin), as is the bone in habitat. If we manipulate the expression of molecules are we propose involved in the process, such as CXCL12 or MCAM in the pMSCs, the mouse bone is black and the habitat is white. This black-and-white result sets the stage for Specific Aim 1 where we dissect the participation of pMSCs and the perivascular basement membrane in driving Skeletal Metastasis. In Specific Aim 2, we propose to determine the participation of HSC-niche ligand molecules expressed on cancer cells in driving SM. We have established a baseline using melanoma, which has the highest rate of lethality once it metastasizes into bone. This proposal will also be focused on the study of molecular mechanisms using breast cancer cell lines. A logical extension of this platform is to provide a predictive diagnostic for the patients' control over metastasis for different osteotropic cancers. In addition to the significant direct clinical impact, this proposed work is expected also to provide the platform for future projects addressing the roles of pMSCs that may influence other skeletal metastasis, such as regulation of local antitumor immune response, cancer cells dormancy and tumor angiogenesis, and to serve as template for the study of other osteotropic malignancies (prostate and lung cancer), thus broadening the significance of the findings and conclusions.

技术摘要 骨骼是从各种肿瘤恶性肿瘤中传播癌症的首选器官。主 该研究建议的目的是了解骨髓微环境的功能，以及 特别是其血管周成分，建立了骨骼转移。 拟议的研究旨在检验间充质干细胞（MSC），，， 作为血管周细胞（PMSC），充当控制肿瘤细胞侵袭骨骼的守门人。这 新假设为临床相关的治疗策略提供了与临床相关的信息 通过关闭转移细胞传输的栅极，减少循环癌细胞的植入 进入正常骨头。我们建议抑制一个或肿瘤细胞和PMSC的组合 特定基因将预防或减弱体内转移过程。 为了实验剖析控制渗出的各种细胞和细胞外基质成分， 我们设计并验证了独特的体内骨骼外骨外式人性化骨骨髓的模仿 平台（人源化的Ossicle）。该平台围绕使用多孔磷酸钙 将人骨骨髓来源的MSC（HBM-MSC）加载到其中，然后植入 免疫缺陷小鼠的背部。骨头由HBM-MSC固定在陶瓷的墙壁上 这些位置以及中心；宿主衍生的血管在骨髓空间内具有PMSC。 我们已经记录到，当黑色素瘤注入小鼠的血液中时，骨骼变成 黑色（黑色素），栖息地中的骨骼也是如此。如果我们操纵分子的表达，我们提出了 参与该过程，例如CXCL12或PMSC中的MCAM，小鼠骨头是黑色的，栖息地为 白色的。这种黑白结果为特定目标1设定了舞台1 驱动骨骼转移的PMSC和血管周围膜。在特定的目标2中，我们 建议确定在癌细胞中表达的HSC-niche配体分子的参与 驾驶SM。 我们已经使用黑色素瘤建立了一个基线，黑色素瘤的致死率最高 进入骨头。该建议还将重点放在使用乳腺癌细胞的分子机制上 线。该平台的逻辑扩展是为患者控制的预测诊断 不同骨癌的转移。 除了重大的直接临床影响外，这项提议的工作还预计还可以提供平台 为了解决可能影响其他骨骼转移的PMSC的作用的未来项目，例如 调节局部抗肿瘤免疫反应，癌细胞休眠和肿瘤血管生成，并使用 作为研究其他骨骼恶性肿瘤（前列腺癌和肺癌）的模板，从而扩大了 发现和结论的意义。