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: 8377423
• 负责人: Laurie K. McCauley
• 金额: $ 23.34万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377423
• 关键词: Affect; Angiogenic Factor; Binding; Biology; Blood Vessels; Bone Growth; Bone Marrow; Bone Marrow Cells; Bone Resorption; CCL2 gene; Cells; Coculture Techniques; Complement; Dependence; Environment; Equilibrium; Event; Growth; Hematopoietic; Hematopoietic stem cells; Homing; Hormones; 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; Osteogenesis; Parathyroid gland; 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 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.

see Instructions）： PTHRP，成骨细胞和骨骼转移性细胞中的造血细胞 前列腺癌（PCA）骨骼转移性病变的微环境富含细胞 支持肿瘤生长。前列腺癌与不稳定的级联菌与失调的骨头互动 吸收和形成。骨微环境中的许多因素都暗示了支持 肿瘤的生长，但现在正在转向影响造血细胞种群的PCA衍生因子 并有助于不稳定的级联。甲状旁腺激素相关蛋白（PTHRP）是肿瘤衍生的 增加血管生成并丰富造血干细胞的骨髓补体的因素 （HSC）和造血祖细胞（HPC）。前列腺癌不是骨头的正常居民 它的存在破坏了骨髓的平衡，但对前列腺之间的串扰知之甚少 癌，骨髓和骨骼的细胞。成骨细胞/基质细胞可能是中心分量 造血成分的主管，血管生成的调节剂，作为骨的介体 病变。总体假设是前列腺癌衍生的PTHRP通过细胞起作用 成骨细胞谱系以支持造血细胞膨胀，而造血细胞膨胀又支持血管生成， 骨髓微环境中的肿瘤生长。 PCA细胞和 造血细胞种群将在骨骼中肿瘤定位期间早期确定 微环境。转移性前列腺癌对骨髓和 PTHRP在支持肿瘤生长至关重要的血管生成中的作用将得到确定。最后 对PTHRP对造血细胞和血管生成的PTHRP影响的成骨细胞/基质细胞的要求将 阐明。这些研究将回答诸如 骨骼转移性病变中的PCA和造血细胞？ PTHRP对 骨骼转移中的血管生成？是PTHRP驱动的造血细胞和血管生成机制 相关？造血和血管生成促进作用是否支持成骨细胞表型？这些 调查结果将提供有价值的策略来开发主要前列腺患者的治疗干预措施 癌可防止骨骼中的肿瘤居留及其毁灭性后果。 相关性（参见Instructions）： 骨髓细胞会影响肿瘤细胞，反之亦然，但实际上对这种相互作用几乎不知道。 该项目将确定前列腺癌蛋白PTHRP在骨髓中的作用及其如何 影响肿瘤生长。更好地了解PTHRP及其在肿瘤微环境中的作用 设计可防止骨骼肿瘤占用的疗法的强大潜力。