Notch Signaling and Prostate Cancer Bone Metastases

Notch信号传导和前列腺癌骨转移

• 批准号: 6944076
• 负责人: Jay M. McDonald
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-27 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944076
• 关键词: athymic mouse; biological signal transduction; bone neoplasms; cell growth regulation; cell line; cell proliferation; clinical research; enzyme induction /repression; human tissue; metastasis; mitogen activated protein kinase; osteoblasts; osteoclasts; pathologic process; polymerase chain reaction; posttranslational modifications; prostate neoplasms; protein protein interaction; stem cells; transcription factor; western blottings

DESCRIPTION (provided by applicant): Prostate cancer (PC) bone metastases are characterized by their ability to induce osteoblastic lesions and local bone formation. The pathophysiology of this skeletal response is not currently known. Many reports have recently shown that osteoblastic metastatic PC cells are osteomimetic and capable of expressing genes and proteins which are known to be expressed by osteoblasts. The Notch signaling pathway plays a pivotal role in determining cell fate. It has been shown that osteoblast differentiation is dependent upon Notch1 activation by DIl1 (Notch ligand) and we have previously demonstrated that Notch1 is responsible for the osteomimetic properties of PC cell lines. Therefore, we hypothesize that prostate carcinoma bone metastases express functional Notch receptors, which are activated in the bone environment resulting in a transformation of prostate carcinoma cells into osteoblast like cells. To test this hypothesis, we will use human PC cell lines which are derived from osteoblastic, osteolytic and mixed metastases, human mesenchymal stem cells, and samples from human prostate bone metastases. The aims of this study are: (1) Characterize the expression of Notch receptors and Notch ligands in metastatic prostate carcinoma. RNA and protein expression will be examined in PC cell lines and human clinical samples. (2) Characterize the molecular mechanisms responsible for osteoblastic transformation of metastatic prostate carcinoma. Western blot and gel shift analysis and transactivation studies will be utilized to elucidate the mechanism. (3) Determine the role of Notch signaling in prostate cancer bone metastasis. Notch activity will be inhibited pharmacologically. The fate of PC cells will be examined in vitro and in a mouse model. Findings from these studies will provide the first documentation of a novel mechanism to explain the ability of prostate cancer's skeletal metastases to induce osteoblastic lesions. A basis will thereby be provided for the development of a new target for drug design and therapeutic intervention to combat the debilitating condition of PC metastases to bone.

描述（由申请人提供）：前列腺癌（PC）骨转移的特征在于其诱导成骨细胞病变和局部骨形成的能力。 目前尚不清楚这种骨骼反应的病理生理学。 最近许多报告表明，成骨细胞转移性PC细胞是仿骨细胞，能够表达已知由成骨细胞表达的基因和蛋白质。 Notch信号通路在决定细胞命运方面发挥着关键作用。 研究表明，成骨细胞分化依赖于 DIl1（Notch 配体）对 Notch1 的激活，并且我们之前已经证明 Notch1 负责 PC 细胞系的仿骨特性。 因此，我们假设前列腺癌骨转移表达功能性Notch受体，该受体在骨环境中被激活，导致前列腺癌细胞转化为成骨细胞样细胞。 为了检验这一假设，我们将使用源自成骨细胞、溶骨细胞和混合转移瘤的人类 PC 细胞系、人类间充质干细胞以及来自人类前列腺骨转移瘤的样本。 本研究的目的是：（1）表征转移性前列腺癌中Notch受体和Notch配体的表达。 将在 PC 细胞系和人类临床样本中检查 RNA 和蛋白质表达。 (2) 描述转移性前列腺癌成骨细胞转化的分子机制。 将利用蛋白质印迹、凝胶位移分析和反式激活研究来阐明其机制。 (3)确定Notch信号在前列腺癌骨转移中的作用。 Notch活性将在药理上受到抑制。 PC 细胞的命运将在体外和小鼠模型中进行检查。 这些研究的结果将为解释前列腺癌骨骼转移诱发成骨细胞病变的能力的新机制提供第一份文献。 因此，将为药物设计和治疗干预的新靶标的开发提供基础，以对抗 PC 骨转移的衰弱状况。