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

重要性：2008年，美国癌症协会预测28，660名男性将死于前列腺癌，使其成为男性癌症死亡的第二大原因。 骨是前列腺癌转移的一个非常常见的部位。 前列腺骨转移促进骨的生长和破坏通过操纵正常宿主细胞的骨称为成骨细胞破骨细胞分别。 因此，患者经常经历剧烈疼痛、自发性骨折和发病率，这极大地影响了他的生活质量。 前列腺骨转移是无法治愈的，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。 理由：我们已经产生了一个独特的前列腺肿瘤诱导的骨生长和破坏的动物模型，准确地模拟了人类疾病。 我们使用该模型分析了前列腺骨肿瘤中数千种基因的表达，发现几种称为基质金属蛋白酶（MMP）的酶以高水平存在（MMP-2，MMP-3，MMP-7，MMP-9和MMP-13），并且它们主要由正常骨细胞表达。 MMPs被认为是基质“推土机”，但PI使用新兴数据提出了一个新概念，即MMPs可以通过改变负责前列腺癌诱导的骨形成和破坏的关键底物（即甲状旁腺相关肽（PTHrP）、核κ B配体受体激活剂（RANKL）和转化生长因子β（TGF？））的活性和可用性来促进细胞间通讯。 基于这些观察结果，我们假设个体宿主来源的MMPs是前列腺肿瘤诱导的骨破坏和骨形成的关键因素，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：在具体目标1中，我们将使用MMP“敲除”动物，使用模拟人类疾病的动物模型测试这些个体骨源性MMP对前列腺肿瘤诱导的骨破坏和形成的贡献。 在具体目标2中，我们将确定MMPs如何通过控制PTHrP和RANKL和TGF？的生物活性和生物利用度来影响前列腺肿瘤诱导的骨变化。 创新与影响：该研究有几个创新点：1）它将首次使用模拟人类疾病的动物模型探索个体宿主来源的MMPs对前列腺肿瘤诱导的骨形成/破坏的贡献; 2）它将首次探索宿主MMPs对前列腺肿瘤-骨微环境中PTHrP，RANKL和TGF？生物活性的影响。 我们提出的研究结果将增强我们对基本肿瘤-骨生物学的理解，改变MMPs如何工作的领域概念，并将揭示可用于治疗前列腺骨转移的潜在新治疗靶点。 公共卫生相关性：在被描述为恶性循环的过程中，前列腺向骨的转移通过分别操纵骨的正常宿主细胞、成骨细胞和破骨细胞而诱导广泛的骨形成和破坏区域。 拟开展的研究将探讨宿主表达的单个基质金属蛋白酶（MMPs）如何通过调节生长因子和细胞因子（如甲状旁腺激素相关肽（PTHrP）、核受体活化因子B配体（RANKL）和转化生长因子（TGF））的生物活性和生物利用度来促进恶性循环的进展。 这些研究将1）增强我们对肿瘤骨生物学的基本理解，并为MMP在肿瘤骨微环境中的作用提供新的见解; 2）鉴定新的MMP底物，其产物可能是新的治疗靶点; 3）将为开发高选择性MMP抑制剂提供理论基础，这些抑制剂没有广谱MMP抑制剂所注意到的有害副作用。

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. PUBLIC HEALTH RELEVANCE: In a process described as the vicious cycle, prostate to bone metastases induce areas of extensive bone formation and destruction by manipulating the normal host cells of the bone, osteoblasts and osteoclasts respectively. The proposed studies will investigate how individual matrix metalloproteinases (MMPs) expressed by the host facilitate the progression of the vicious cycle by regulating the bioactivity and bioavailability of growth factors and cytokines such as parathyroid hormone related peptide (PTHrP), receptor activator of nuclear kappa B ligand (RANKL) and transforming growth factor ¿ (TGF¿). This studies will 1) enhance our basic understanding of tumor bone biology and provide new insights into the roles for MMPs in the tumor bone microenvironment; 2) identify novel MMP substrates, the products of which can potentially be new therapeutic targets and 3) will provide a rationale for the development of highly selective MMP inhibitors that lack the deleterious side effects noted with broad spectrum MMP inhibitors.