Host MMP-mediated regulation of the vicious cycle of prostate to bone metastases

描述(申请人提供)：意义：2008年，美国癌症协会预测，将有28,660名男性死于前列腺癌，使其成为男性癌症死亡的第二大原因。骨骼是前列腺癌转移的一个非常常见的部位。前列腺到骨的转移通过分别操纵正常的骨宿主细胞，即成骨细胞和破骨细胞，促进骨的生长和破坏。因此，患者经常经历剧烈的疼痛、自发性骨折和发病率，这些都极大地影响了他的生活质量。前列腺到骨的转移是无法治愈的，目前的治疗选择有限。为了确定新的治疗靶点，需要全面了解前列腺肿瘤细胞如何与正常骨细胞沟通，以诱导骨生长和破坏。理论基础：我们已经建立了一种独特的前列腺癌诱导的骨生长和破坏的动物模型，准确地模拟了人类的疾病。我们使用该模型分析了数千个基因在前列腺骨肿瘤中的表达，发现几种被称为基质金属蛋白酶(MMPs)的酶(MMPs)存在于高水平(MMP2、MMP3、MMP7、MMP9和MMP13)中，并且主要在正常骨细胞中表达。MMPs被认为是基质的推土机，但使用新兴数据的PI提出了一个新的概念，即MMPs可以通过改变导致前列腺癌诱导的骨形成和破坏的关键底物的活性和可用性来促进细胞间的沟通，这些底物是甲状旁腺相关肽(PTHrP)、核Kappa B受体激活剂B配体(RANKL)和转化生长因子β(TGF)。基于这些观察，我们假设单个宿主来源的MMPs是前列腺癌诱导的骨破坏和骨形成的关键贡献者，因为它们能够调节控制前列腺癌-骨通讯的因子的活性。方法：在特定的目标1中，我们将使用基质金属蛋白酶“基因敲除”动物，利用模拟人类疾病的动物模型，测试这些单独的骨源性基质金属蛋白酶在前列腺癌诱导的骨破坏和形成中的作用。在具体目标2中，我们将通过控制PTHrP、RANKL和转化生长因子的生物活性和生物利用度来确定MMPs如何影响前列腺癌引起的骨骼变化。创新和影响：拟议的研究有几个创新：1)首次利用模拟人类疾病的动物模型探索单个宿主来源的MMPs在前列腺癌诱导的骨形成/破坏中的作用；2)首次探讨宿主MMPs对前列腺癌-骨微环境中PTHrP、RANKL和TGFβ生物活性的影响。我们提出的研究结果将增强我们对基础肿瘤-骨生物学的理解，改变该领域关于MMPs如何发挥作用的概念，并将揭示潜在的新治疗靶点，可用于治疗男性前列腺癌到骨转移。

DESCRIPTION (provided by applicant): Significance: In 2008 the American Cancer Society predicted that 28,660 men will die from prostate cancer making it the second leading cause of cancer death in men. Bone is an extremely common site for prostate cancer metastasis. Prostate to bone metastases promote bone growth and destruction by manipulating normal host cells of the bone known as osteoblasts osteoclasts respectively. As a result, the patient often experiences intense pain, spontaneous fractures and morbidity that dramatically affect his quality of life. Prostate to bone metastases are incurable and the current treatment options are limited. In order to identify new therapeutic targets, a comprehensive understanding of how the prostate tumor cells communicate with the normal bone cells to induce bone growth and destruction is required. Rationale: We have generated a unique animal model of prostate tumor induced bone growth and destruction that accurately mimics the human disease. We have used the model to analyze the expression of thousands of genes in prostate bone tumors and have found that several enzymes known as matrix metalloproteinases (MMPs) are present at high levels (MMP-2, MMP-3, MMP-7, MMP-9 and MMP-13) and that they are predominantly expressed by the normal bone cells. MMPs are considered matrix 'bulldozers' but the PI using emerging data proposes a new concept that MMPs can facilitate cell-cell communication by altering the activity and availability of key substrates responsible for prostate cancer induced bone formation and destruction, namely parathyroid related peptide (PTHrP), receptor activator of nuclear kappa B ligand (RANKL) and transforming growth factor beta (TGF¿). Based on these observations, we hypothesize that individual host derived MMPs are key contributors to prostate tumor induced bone destruction and bone formation by virtue of their ability to regulate the activity of factors that control prostate cancer-bone communication. Approaches: In Specific Aim 1, we will use MMP 'knockout' animals test the contribution of these individual bone derived MMPs to prostate tumor induced bone destruction and formation using animal models that mimic the human disease. In Specific Aim 2, we will determine how MMPs can impact prostate tumor induced changes in the bone by controlling the bioactivity and bioavailability of PTHrP and RANKL and TGF¿. Innovation and Impact: The proposed study has several innovations; 1) It will be the first to explore the contribution of individual host derived MMPs to prostate tumor induced bone formation/destruction using animal models that mimic the human disease; 2) It will be the first to explore the impact of host MMPs on the bioactivity of PTHrP, RANKL and TGF¿ in the prostate tumor-bone microenvironment. The results of our proposed studies will enhance our understanding of basic tumor-bone biology, change the concept of the field as to how MMPs work and will reveal potentially new therapeutic targets that can be used to treat men with prostate to bone metastases.