RANKL and BMPs in Prostate Cancer Induced Bone Lesions

描述（由申请人提供）： 前列腺癌骨转移与显著的发病率相关，并且不能用当前的治疗方案治愈。由于对前列腺癌（PC）骨转移的病理生理学了解甚少，因此很难确定适当的治疗方式。在以前的研究中，我们注意到诱导成骨细胞病变的PC细胞表达与溶骨性病变相关的PC细胞不同的细胞因子。这表明不同的信号通路负责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建立肿瘤细胞向骨内渗透所必需的。我们的目标是提高我们对前列腺癌细胞和骨之间的生物学相互作用的理解，以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BMP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。在特定目的1中，我们将通过向SCID小鼠给予RANKFc，确定RANK抑制对骨中成骨细胞、溶骨性和混合性病变形成的作用。《特定目标2》中提出的研究将检验肿瘤细胞分泌的BMP在成骨细胞病变中观察到的骨形成中发挥作用的假设。前列腺癌细胞系将用表达BMP拮抗剂头蛋白的逆转录病毒载体稳定转染。在特定目标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。将在Aim 2中生成的表达Noggin的PC细胞注射到接受RANKFc处理的SCID小鼠的胫骨中。这些实验将鉴定显性转移表型或阐明有效治疗肿瘤骨转移的新型联合疗法。这项拟议的研究应使我们能够确定RANKL和BMP在骨中肿瘤诱导的溶骨性、成骨细胞性或混合性病变发展中的作用，并有望使我们在确定预防或限制前列腺癌骨转移的潜在治疗发病率方面更进一步。

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.