PTHrP, Osteoblasts and Hematopoietic Cells in the Sketletal Metastic Niche

骨骼转移微环境中的 PTHrP、成骨细胞和造血细胞

• 批准号: 7659015
• 负责人: Laurie K. McCauley
• 金额: $ 20.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-05 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659015
• 关键词: Affect; Angiogenic Factor; Binding; Biology; Blood Vessels; Bone Growth; Bone Marrow; Bone Marrow Cells; Bone Resorption; Cells; Coculture Techniques; Complement; Dependence; Environment; Equilibrium; Event; Growth; Hematopoietic; Hematopoietic stem cells; Homing; Lesion; Malignant Epithelial Cell; Malignant neoplasm of prostate; Marrow; Mediator of activation protein; Metastatic Lesion; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Neoplasm Metastasis; Occupations; Osteoblasts; Osteoclasts; Parathyroid Hormones; Pathway interactions; Patients; Phenotype; Population; Principal Investigator; Proliferating; Prostate carcinoma; Proteins; Residencies; Role; Scheme; Signal Transduction; Site; Skeleton; Stem cells; Stromal Cells; Supporting Cell; Therapeutic Intervention; Tumor Angiogenesis; Tumor-Derived; angiogenesis; bone; bone turnover; cancer cell; cell growth; chemokine; human PTH protein; human data; in vitro Assay; interest; irradiation; mouse model; neoplastic cell; novel; parathyroid hormone-related protein; prevent; receptor; skeletal; therapy design; tumor; tumor growth

Seeinstructions): PTHrP, osteoblasts and hematopoietic cells in the skeletal metastatic niche The microenvironment of the skeletal metastatic lesion of prostate carcinoma (PCa) is rich in cells that support tumor growth. Prostate carcinoma engages this niche in an unstable cascade with deregulated bone resorption and formation. Numerous factors in the bone microenvironment have been implicated that support tumor growth but interest is now turning to PCa derived factors that impact the hematopoietic cell population and contribute to the unstable cascade. Parathyroid hormone related protein (PTHrP) is a tumor-derived factor that increases angiogenesis and enriches the bone marrow complement of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Prostate carcinoma is not a normal inhabitant of bone and its presence disrupts the equilibrium of the marrow, but little is known of the crosstalk between prostate carcinoma, cells of the marrow and bone. The osteoblast/stromal cell is likely a central component as a director of the hematopoietic component, a regulator of angiogenesis, and as the mediator of the osseous lesion. The overall hypothesis is that prostate cancer-derived PTHrP acts through cells of the osteoblast lineage to support hematopoietic cell expansion which in turn supports angiogenesis, and tumor growth in the bone marrow microenvironment. The reciprocal impact of PCa cells and hematopoietic cell populations will be determined early during tumor localization in the skeletal microenvironment. The impact of metastatic prostate carcinoma on angiogenesis in the bone marrow and the role of PTHrP in supporting the angiogenesis critical for tumor growth will be determined. Finally the requirement of osteoblasts/stromal cells for the PTHrP impact on hematopoietic cells and angiogenesis will be elucidated. These studies will answer outstanding questions such as what is the relationship between PCa and hematopoietic cells in the skeletal metastatic lesion? What is the contribution of PTHrP to angiogenesis in skeletal metastasis? Are PTHrP-driven hematopoietic cells and angiogenic mechanisms inter-related? Do hematopoietic and angiogenic promoting effects support an osteoblastic phenotype? These findings will provide valuable strategies to develop therapeutic interventions in patients with primary prostate carcinoma to prevent tumor residency in the skeleton and its devastating consequences. RELEVANCE (Seeinstructions): Bone marrow cells impact the tumor cells and visa versa, but little is actually known of such interactions. This project will determine the role of the prostate cancer protein, PTHrP, in the bone marrow and how it affects tumor growth. A better understanding of PTHrP and its role in the tumor microenvironment has strong potential for designing therapies that prevent tumor occupation of the skeleton.

参见说明）： 骨转移灶中PTHrP、成骨细胞和造血细胞的研究 前列腺癌（PCa）骨转移病灶的微环境富含细胞， 支持肿瘤生长。前列腺癌在骨失调的不稳定级联反应中参与了这个小生境 再吸收和形成。骨微环境中的许多因素都涉及支持 但是现在的兴趣转向了影响造血细胞群的PCa衍生因子 导致了不稳定的级联反应甲状旁腺激素相关蛋白（PTHrP）是一种肿瘤源性蛋白， 一种增加血管生成并富集造血干细胞的骨髓补体的因子 造血干细胞（HSC）和造血祖细胞（HPC）。前列腺癌不是正常的骨骼寄生物 它的存在破坏了骨髓的平衡，但很少有人知道前列腺之间的串扰， 癌，骨髓和骨的细胞。成骨细胞/基质细胞可能是骨形成的核心成分。 造血成分的导演，血管生成的调节器，并作为骨的介质 损伤。总体假设是前列腺癌来源的PTHrP通过前列腺上皮细胞起作用。 成骨细胞谱系以支持造血细胞扩增，而造血细胞扩增又支持血管生成， 和肿瘤在骨髓微环境中的生长。前列腺癌细胞和 造血细胞群将在肿瘤定位于骨骼中的早期确定， 微环境转移性前列腺癌对骨髓血管生成的影响 将确定PTHrP在支持对肿瘤生长至关重要的血管生成中的作用。最后 PTHrP对造血细胞和血管生成的影响需要成骨细胞/基质细胞， 被阐明。这些研究将回答一些悬而未决的问题，例如： 骨转移灶中PCa和造血细胞的关系？PTHrP的作用是什么？ 骨转移中的血管生成PTHrP驱动的造血细胞和血管生成机制 相互关联？造血和血管生成促进作用支持成骨细胞表型吗？这些 研究结果将为原发性前列腺疾病患者的治疗干预提供有价值的策略 癌症，以防止肿瘤驻留在骨骼及其破坏性后果。 相关性（参见说明）： 骨髓细胞影响肿瘤细胞，反之亦然，但实际上对这种相互作用知之甚少。 该项目将确定前列腺癌蛋白PTHrP在骨髓中的作用，以及它是如何在骨髓中发挥作用的。 影响肿瘤生长。更好地了解PTHrP及其在肿瘤微环境中的作用， 设计防止肿瘤占据骨骼的疗法的强大潜力。