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转移的首选器官。主要 本研究计划的目的是了解骨髓微环境的功能， 特别是其血管周围成分，在骨转移的建立中。 所提出的研究旨在测试间充质干细胞（MSC）， 作为血管周围细胞（pMSC），作为控制肿瘤细胞侵入骨的看门人。这 新的假设为治疗策略提供了临床相关信息， 通过关闭转移性细胞通过的门来减少循环癌细胞的植入 进入正常的骨骼我们提出，肿瘤细胞和pMSC之一或组合的抑制可以通过抑制肿瘤细胞和pMSC中的一种或组合来实现。 特异性基因将阻止或减弱体内转移过程。 为了实验性地解剖控制外渗的各种细胞和细胞外基质成分， 我们已经设计并验证了一种独特的体外人源化骨髓小生境模拟 平台（人源化小骨）。这个平台是围绕使用多孔，磷酸钙 将人骨髓来源的MSC（hBM-MSC）加载到陶瓷中，然后植入陶瓷中。 免疫缺陷小鼠的背部。骨通过锚定在陶瓷壁上的hBM-MSC制造， 在这些位置和中心，宿主来源的血管在骨髓空间内具有pMSC。 我们已经证明，当黑色素瘤被注射到老鼠的血液中时， 黑色（黑色素），就像栖息地的骨头。如果我们操纵分子的表达， 参与该过程的，例如pMSC中的CXCL 12或MCAM，小鼠骨骼是黑色的，栖息地是 白色。这个非黑即白的白色结果为具体目标1奠定了基础，在具体目标1中，我们剖析了 pMSC和血管周围基底膜在驱动骨转移中的作用。在具体目标2中， 建议确定在癌细胞上表达的HSC-小生境配体分子参与 驾驶SM。 我们已经建立了一个使用黑色素瘤的基线，黑色素瘤一旦转移，致死率最高 变成骨头该提案还将集中在使用乳腺癌细胞的分子机制的研究上。 线这个平台的一个逻辑扩展是为患者提供一个预测性诊断， 不同的骨转移癌。 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pMSCs的作用，可能会影响其他骨骼转移，如 调节局部抗肿瘤免疫应答、癌细胞休眠和肿瘤血管生成， 作为其他骨恶性肿瘤（前列腺癌和肺癌）研究的模板，从而拓宽了 调查结果和结论的重要性。