RANKL and BMPs in Prostate Cancer Induced Bone Lesions

描述(由申请人提供)： 前列腺癌的骨转移与显著的发病率有关，目前的治疗方案不能治愈。由于前列腺癌(PC)骨转移的病理生理学机制尚不清楚，因此很难找到合适的治疗方法。在以前的研究中，我们已经注意到诱导成骨细胞损伤的PC细胞与与溶骨性损伤相关的PC细胞表达不同的细胞因子。这表明不同的信号通路在成骨细胞和溶骨性病变的形成中起重要作用。此外，我们的数据还表明，破骨细胞的活性可能不是建立肿瘤细胞进入骨骼所必需的。我们的目标是加强我们对前列腺癌细胞和骨之间的生物相互作用的了解，以便最终确定可以限制或抑制转移过程的潜在治疗方式。我们提出的假设是PC细胞表达RANK配体和/或BMPs直接控制骨转移灶的表型。因此，我们将在SCID小鼠的胫骨注射模型中确定RANKL和BMP抑制对人PC骨损伤形成的影响。在具体目标1中，我们将通过给SCID小鼠注射RANKFc来确定RANKFc对成骨细胞、溶骨性和混合性骨损伤形成的RANK抑制作用。发表在《特定目标2》上的这项研究将检验这样一种假设，即肿瘤细胞分泌的BMPs在成骨细胞病变中的骨形成中发挥作用。表达BMP拮抗剂Noggin的逆转录病毒载体将稳定地转染前列腺癌细胞系。在具体目标3中，我们将确定BMP抑制和RANK阻断对成骨细胞和溶骨性骨损伤形成的影响。在AIM 2中产生的表达Noggin的PC细胞将被注射到经RANKFc治疗的SCID小鼠的胫骨中。这些实验将要么确定主要的转移表型，要么阐明一种有效治疗肿瘤骨转移的新的联合疗法。这项拟议的研究将使我们能够确定RANKL和BMPs在肿瘤引起的骨溶解、成骨细胞或混合性病变的发生中所起的作用，并有望使我们在确定预防或限制前列腺癌向骨转移的潜在治疗方法方面更近一步。

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.