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

宿主MMP介导的前列腺骨转移恶性循环的调节

• 批准号: 8232258
• 负责人: Conor C Lynch
• 金额: $ 30.25万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232258
• 关键词: Adverse effects; Affect; American Cancer Society; Animal Model; Animal Testing; Animals; Area; Behavior; Binding Proteins; Biological Availability; Biology; Bone Growth; Bone neoplasms; Bone remodeling; Cancer Etiology; Cell Communication; Cells; Cessation of life; Clinical; Communication; Data; Development; Differentiation and Growth; Enzymes; Event; Extracellular Matrix; Gelatinase A; Gelatinase B; Genes; Growth; Growth Factor; Health; Human; Individual; Knockout Mice; Lesion; Ligands; Light; Malignant neoplasm of prostate; Matrilysin; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Metastatic Neoplasm to the Bone; Modeling; Morbidity - disease rate; Neoplasm Metastasis; Nuclear; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Osteolytic; Parathyroid Hormone Receptor; Parathyroid gland; Pathological fracture; Patients; Peptide Receptor; Peptides; Procedures; Process; Prostate; Prostatic Neoplasms; Quality of life; Regulation; Resolution; Rodent Model; Role; Site; Stromelysin 1; Surface; Technology; Testing; Therapeutic; Time; Transforming Growth Factor beta; Transforming Growth Factors; Work; base; bone; bone cell; collagenase 3; cytokine; experience; human disease; innovation; insight; intense pain; knockout animal; men; neoplastic cell; new therapeutic target; novel; novel therapeutics; osteoclastogenesis; receptor; response; single photon emission computed tomography; tumor growth

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.

描述（由适用提供）：意义：2008年，美国癌症协会预测，有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主要原因。骨是前列腺癌转移的极为常见的部位。通过操纵称为成骨细胞的骨骼的正常宿主细胞来促进骨转移酶的前列腺。结果，患者经常会遭受剧烈的疼痛，赞助的骨折和发病率，这极大地影响了他的生活质量。前列腺对骨转移量是无法治愈的，并且当前的治疗选择受到限制。为了确定新的治疗靶标，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骼生长和破坏。基本原理：我们已经产生了一种独特的动物模型，以诱发骨骼生长和破坏，以准确地模仿人类疾病。我们已经使用该模型来分析前列腺骨肿瘤中数千种基因的表达，并发现几种称为基质金属蛋白酶（MMP）的酶在高水平（MMP-2，MMP-3，MMP-7，MMP-7，MMP-9和MMP-13）上存在，并且由正常的骨细胞表达了正常的骨细胞。 MMP被认为是矩阵“ Buldozers”，但是使用新兴数据的PI提出了一个新概念，MMP可以通过改变负责前列腺癌引起的骨骼形成的关键底物的活动和可用性来促进细胞细胞的通信，而副甲状腺功能相关的肽（PTHRP），核kappa beta and carkappa beta and carkappa berand cropter（pthrp），cangappa beta bern carkappa bern bern carkappa beta bern bere and。 ）。基于这些观察结果，我们假设单个宿主衍生的MMP是前列腺肿瘤诱导的骨骼破坏和骨形成的关键因素，因为它们可以调节控制前列腺癌骨通信的因素的活性。方法：在特定的目标1中，我们将使用MMP“敲除”动物测试这些单个骨衍生的MMP对前列腺肿瘤诱导骨骼破坏和形成的贡献，该动物使用模仿人类疾病的动物模型。在特定的目标2中，我们将通过控制PTHRP和RANKL和TGF¿的生物活性和生物利用度来确定MMP如何影响前列腺肿瘤诱导的骨骼变化。创新和影响：拟议的研究有几项创新； 1）这将是第一个使用模仿人类疾病的动物模型探索单个宿主衍生的MMP对前列腺肿瘤诱导骨形成/破坏的贡献的人； 2）这将是第一个探索宿主MMP对PTHRP，RANKL和TGF缺在前列腺肿瘤骨微环境中生物活性的影响。我们提出的研究的结果将增强我们对基本肿瘤骨生物学的理解，改变有关MMP如何工作的领域概念，并将揭示可用于治疗前列腺转移的男性的潜在新的治疗靶标。