PTHrP, Osteoblasts and Hematopoietic Cells in the Sketletal Metastic Niche

请参阅说明)： 甲状旁腺激素受体、成骨细胞和造血细胞在骨转移灶中的表达 前列腺癌(PCa)骨转移灶微环境中含有丰富的细胞 支持肿瘤生长。前列腺癌以一种不稳定的级联反应与骨质疏松相结合。 吸收和形成。骨骼微环境中的许多因素都被认为是支持 肿瘤生长，但现在人们的兴趣转向影响造血细胞数量的PCA衍生因子 并促成了不稳定的瀑布。甲状旁腺激素相关蛋白(PTHrP)是一种来源于肿瘤的 促进血管生成和丰富骨髓造血干细胞补体的因子 (HSCs)和造血祖细胞(HPC)。前列腺癌不是正常的骨骼居住者。 它的存在会扰乱骨髓的平衡，但人们对前列腺之间的串扰知之甚少 癌症，骨髓和骨的细胞。成骨细胞/基质细胞可能是一种 造血部分的主管，是血管生成的调节器，也是骨的媒介 损伤。总体假设是前列腺癌来源的PTHrP通过 成骨细胞谱系支持造血细胞扩张，而造血细胞扩张又支持血管生成， 和骨髓微环境中的肿瘤生长。PCa细胞和Pca细胞的相互影响 在骨骼中肿瘤定位的早期将确定造血细胞的数量 微环境。转移性前列腺癌对骨髓和骨髓血管生成的影响 PTHrP在支持对肿瘤生长至关重要的血管生成中的作用将被确定。最后是 成骨细胞/基质细胞对甲状旁腺素相关蛋白对造血细胞和血管生成的影响 将被澄清。这些研究将回答一些悬而未决的问题，如 骨转移灶中的Pca和造血细胞？PTHrP对以下方面有何贡献 骨转移瘤中的血管生成？甲状旁腺素相关蛋白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 研究结果将为发展对原发性前列腺癌患者的治疗干预提供有价值的策略。 癌症可防止肿瘤滞留在骨骼及其破坏性后果。 相关性(请参阅说明)： 骨髓细胞影响肿瘤细胞，反之亦然，但人们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 会影响肿瘤的生长。更好地了解甲状旁腺素受体及其在肿瘤微环境中的作用 在设计防止肿瘤侵占骨骼的疗法方面具有很强的潜力。

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.