RANKL and BMPs in Prostate Cancer Induced Bone Lesions

RANKL 和 BMP 在前列腺癌引起的骨病变中的作用

• 批准号: 6795485
• 负责人: JAY R. LIEBERMAN
• 金额: $ 34.19万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795485
• 关键词: SCID mouse; bone disorder; bone morphogenetic proteins; cell line; glycoproteins; growth inhibitors; membrane transport proteins; metastasis; morphometry; neoplastic cell; osteoblasts; osteoclasts; osteogenesis; prostate neoplasms; protein structure function; radiography; tibia; transfection /expression vector

DESCRIPTION (provided by applicant): Prostate cancer metastasis to bone is associated with significant morbidity and is not curable with current treatment regimens. Since the pathophysiology of prostate cancer (PC) metastasis to bone is poorly understood it has been difficult to identify appropriate treatment modalities. In previous studies we have noted that PC cells that induce osteoblastic lesions express different cytokines than PC cells associated with osteolytic lesions. This suggests that different signaling pathways are responsible for the formation of osteoblastic and osteolytic lesions. In addition, our data also suggests that osteoclast activity may not be necessary to establish tumor cell intravasation into bone. Our goal is to enhance our understanding of the biological interaction between prostate cancer cells and bone in order to eventually identify potential treatment modalities that can limit or inhibit the metastatic process. We propose the hypothesis that PC cell expression of RANK-ligand and/or BMPs directly control the phenotype of metastatic bone lesions. Therefore, we will determine the influence of RANKL and BMP inhibition on the formation of human PC bone lesions in a tibial injection model in SCID mice. In Specific Aim 1 we will determine the role of RANK inhibition on the formation of osteoblastic, osteolytic, and mixed lesions, in bone by administering RANKFc to the SCID mice. The research proposed in Specific Aim 2 will test the hypothesis that BMPs secreted by tumor cells play a role in the bone formation seen in osteoblastic lesions. Prostate cancer cell lines will be stably transfected with a retroviral vector expressing the BMP antagonist Noggin. In Specific Aim 3, we will determine the influence of both BMP inhibition and RANK blockade on the formation of osteoblastic and osteolytic lesions in bone. The Noggin expressing PC cells generated in Aim 2 will be injected into the tibias of SCID mice that are treated with RANKFc. These experiments will either identify the dominant metastatic phenotype or elucidate a novel combination therapy to effectively treat tumor metastasis to bone. This proposed research should enable to us to identify the role that RANKL and BMPs play on the development of tumor induced osteolytic, osteoblastic or mixed lesions in bone and hopefully will take us a step closer in identifying potential treatment mordalities to prevent or limit metastatic prostate cancer to bone.

描述（由申请人提供）： 前列腺癌骨转移与显着的发病率相关，并且当前的治疗方案无法治愈。由于对前列腺癌（PC）骨转移的病理生理学知之甚少，因此很难确定适当的治疗方式。在之前的研究中，我们注意到诱导成骨细胞病变的 PC 细胞表达的细胞因子与与溶骨性病变相关的 PC 细胞不同。这表明不同的信号通路导致成骨细胞和溶骨性病变的形成。此外，我们的数据还表明，破骨细胞活性可能不是肿瘤细胞侵入骨所必需的。我们的目标是增强对前列腺癌细胞和骨之间生物相互作用的理解，以便最终确定可以限制或抑制转移过程的潜在治疗方式。我们提出这样的假设：RANK 配体和/或 BMP 的 PC 细胞表达直接控制转移性骨病变的表型。因此，我们将在 SCID 小鼠胫骨注射模型中确定 RANKL 和 BMP 抑制对人 PC 骨病变形成的影响。在具体目标 1 中，我们将通过给 SCID 小鼠施用 RANKFc 来确定 RANK 抑制对骨中成骨细胞、溶骨性和混合病变形成的作用。具体目标 2 中提出的研究将检验肿瘤细胞分泌的 BMP 在成骨细胞病变中骨形成中发挥作用的假设。前列腺癌细胞系将用表达 BMP 拮抗剂 Noggin 的逆转录病毒载体稳定转染。在具体目标 3 中，我们将确定 BMP 抑制和 RANK 阻断对骨中成骨细胞和溶骨性病变形成的影响。在 Aim 2 中生成的表达 Noggin 的 PC 细胞将被注射到用 RANKFc 处理的 SCID 小鼠的胫骨中。这些实验将确定主要的转移表型，或阐明一种新的联合疗法，以有效治疗肿瘤骨转移。这项拟议的研究应该使我们能够确定 RANKL 和 BMP 在骨中肿瘤诱导的溶骨性、成骨性或混合性病变的发展中所发挥的作用，并有望使我们在确定预防或限制转移性前列腺癌的潜在治疗方式方面更近一步。到骨头。