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: 10248515
• 负责人: Arnold Irwin Caplan
• 金额: $ 36.83万
• 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/10248515
• 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 骨骼是各种恶性肿瘤传播癌症的首选器官。主要 本研究计划的目的是了解骨髓微环境的功能，以及 特别是其血管周围成分，在骨骼转移的建立中。 所提出的研究旨在测试间充质干细胞（MSC）的创新假设， 作为血管周围细胞（pMSC），充当控制肿瘤细胞侵入骨骼的看门人。这 新的假设为创新性的治疗策略提供了临床相关信息 通过关闭转移细胞转运的大门来减少循环癌细胞的植入 进入正常骨骼。我们建议抑制肿瘤细胞和 pMSC 中的一种或组合 特定基因会阻止或减弱体内转移过程。 为了通过实验剖析控制外渗的各种细胞和细胞外基质成分， 我们设计并验证了一种独特的体内骨骼外人源化骨髓生态位模仿 平台（人性化小骨）。该平台以多孔磷酸钙的使用为中心 陶瓷中装载人骨髓来源的间充质干细胞（hBM-MSC），然后植入 免疫缺陷小鼠的背部。骨骼由锚定在陶瓷壁上的 hBM-MSC 制作而成 这些地点以及中心；宿主来源的血管在骨髓腔内有 pMSC。 我们已经记录到，当黑色素瘤被注射到小鼠的血流中时，骨头就会变成 黑色（黑色素），就像骨头的栖息地一样。如果我们操纵分子的表达，我们建议 参与该过程的，如pMSCs中的CXCL12或MCAM，小鼠骨骼为黑色，栖息地为 白色的。这个黑白分明的结果为具体目标 1 奠定了基础，我们在其中剖析了以下人员的参与： pMSCs 和血管周围基底膜驱动骨骼转移。在具体目标 2 中，我们 提议确定癌细胞上表达的 HSC-niche 配体分子参与 驾驶SM。 我们已经使用黑色素瘤建立了基线，黑色素瘤一旦转移，致死率最高 进入骨头。该提案还将重点研究利用乳腺癌细胞的分子机制 线。该平台的逻辑扩展是为患者的控制提供预测诊断 不同骨癌的转移。 除了重大的直接临床影响外，这项拟议的工作预计还将提供平台 对于未来的项目，解决可能影响其他骨骼转移的 pMSC 的作用，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，并服务 作为研究其他骨性恶性肿瘤（前列腺癌和肺癌）的模板，从而拓宽了研究范围 研究结果和结论的重要性。