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

基本信息

批准号：
8657863
负责人：
Conor C Lynch
金额：
$ 29.2万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657863
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 Figs - dietary Gelatinase A Gelatinase B Genes Growth Factor 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

项目摘要

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 metastses.

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原因。骨头是前列腺的极为常见的位置癌症转移。通过操纵正常的前列腺向骨转移酶促进骨骼生长和破坏骨骼的宿主细胞分别称为成骨细胞。结果，患者经常经历强烈的疼痛，赞助骨折和发病率极大地影响了他的生活质量。前列腺到骨头转移是无法治愈的，并且当前的治疗方案受到限制。为了识别新疗法目标，对前列腺肿瘤细胞如何与正常骨通信的全面了解需要诱导骨骼生长和破坏的细胞。理由：我们已经产生了一种独特的前列腺肿瘤动物模型这可以准确地模仿人类疾病。我们已经使用该模型分析了数千个的表达前列腺骨肿瘤中的基因，发现几种称为基质金属蛋白酶的酶（MMP）存在于高水平（MMP-2，MMP-3，MMP-7，MMP-9和MMP-13），它们是主要由正常骨细胞表达。 MMP被视为矩阵“ Buldozers”，但使用PI 新兴数据提案提出了一个新概念，MMP可以通过更改活动来促进细胞电池通信以及负责前列腺癌引起的骨形成和破坏的关键基材的可用性，即甲状旁腺相关肽（PTHRP），核Kappa B配体的接收器激活剂（RANKL）和改变生长因子β（TGF¿）。基于这些观察结果，我们假设该单个主机派生的MMP是前列腺肿瘤引起的骨骼破坏和骨形成的关键因素他们调节控制前列腺癌骨通信的因素活性的能力。方法：在特定目标1中，我们将使用MMP“淘汰”动物测试这些人的贡献骨衍生的MMP到前列腺肿瘤诱导骨破坏和形成，使用模仿动物模型人类疾病。在特定的目标2中，我们将确定MMP如何影响前列腺肿瘤通过控制PTHRP和RANKL和TGF¿的生物活性和生物利用度来改变骨骼。创新和影响：拟议的研究有几项创新； 1）这将是第一个探索单个宿主衍生的MMP对前列腺肿瘤诱导的骨形成/破坏的贡献模仿人类疾病的动物模型； 2）这将是第一个探索主机MMP对前列腺肿瘤骨微环境中PTHRP，RANKL和TGF¿的生物活性。我们的结果拟议的研究将增强我们对基本肿瘤生物学的理解，改变现场的概念至于MMP的工作方式，并将揭示潜在的新治疗靶标的，这些靶标可用于治疗男性前列腺向骨转移。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth.

DOI：
10.1158/1535-7163.mct-16-0315-t
发表时间：
2017-03
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Tauro M;Shay G;Sansil SS;Laghezza A;Tortorella P;Neuger AM;Soliman H;Lynch CC
通讯作者：
Lynch CC

Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer.

DOI：
10.1038/srep29384
发表时间：
2016-07-14
期刊：
Scientific reports
影响因子：
4.6
作者：
Cook LM;Araujo A;Pow-Sang JM;Budzevich MM;Basanta D;Lynch CC
通讯作者：
Lynch CC

Improving treatment strategies for patients with metastatic castrate resistant prostate cancer through personalized computational modeling.

DOI：
10.1007/s10585-014-9674-1
发表时间：
2014-12
期刊：
Clinical & experimental metastasis
影响因子：
4
作者：
Gallaher J;Cook LM;Gupta S;Araujo A;Dhillon J;Park JY;Scott JG;Pow-Sang J;Basanta D;Lynch CC
通讯作者：
Lynch CC

An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer.