PROSTATE CANCER BONE METASTASES: ROLE OF ADRENOMEDULLIN

前列腺癌骨转移：肾上腺髓质素的作用

基本信息

批准号：
7391126
负责人：
THERESA A GUISE
金额：
$ 33.3万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7391126
关键词：
Animal Model Apoptosis Biological Assay Bone Matrix Bone Resorption Bone remodeling Breast Calvaria Cancer Model Cell physiology Cells Characteristics Clinical Complex Data Development Goals Growth Growth Factor In Vitro Innate Bone Remodeling Intervention Malignant neoplasm of lung Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Mus Neoplasm Metastasis Osteoblasts Osteoclasts Osteogenesis Patients Physiological Process Production Protein Overexpression Proteins Role Sampling Signal Pathway Site Solid Neoplasm Statistically Significant Testing Therapeutic Intervention Treatment Efficacy Tumor Angiogenesis adrenomedullin angiogenesis autocrine base bisphosphonate bone bone cell cancer cell cell motility in vivo inhibitor/antagonist loss of function neoplastic cell paracrine polypeptide release factor research study response soft tissue tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Adrenomedullin [AM] is a polypeptide secreted by prostate cancers and potent stimulator of bone formation and osteoblast proliferation. It also proangiogenic and antiapoptotic for tumor cells, thus having autocrine and paracrine roles in bone metastases. We propose that AM from prostate cancer cells contributes to a vicious cycle of bone metastasis by: 1) paracrine stimulation of osteoblast proliferation and tumor angiogenesis, and 2) autocrine effects on the tumor cells. We propose that AM production by prostate cancer is increased by growth factors in bone, which is a major storage site for immobilized growth factors: these are released by osteoclastic bone resorption and are also synthesized by osteoblasts. Both processes are increased by metastatic tumor cells. Bone-derived factors stimulate tumor cells to grow, as well as to produce more factors that stimulate osteoblasts and bone resorption, causing a vicious cycle characteristic of bone metastases. The release of factors from bone into the microenvironment can be decreased by bisphosphonate inhibitors of bone resorption. Our preliminary data support a role for AM in bone metastases: 1) AM is a potent stimulator of new bone formation in a mouse calvarial assay; 2) loss of function of AM decreased bone metastases in a lung cancer model; and 3) prostate cancer cells overexpressing AM had accelerated bone metastases and showed osteoblastic responses. We propose four hypotheses: a) Adrenomedullin increases prostate cancer bone metastases b) Tumor AM is increased in bone versus soft tissue metastases c) AM has autocrine growth and paracrine angiogenic effects on prostate cancer cells d) Tumor-secreted AM stimulates bone by increasing osteoblast proliferation We propose to test these hypotheses with Three Specific Aims: Aim 1: Determine the effects of tumor adrenomedullin on bone metastases Aim 2: Determine changes in AM expression caused by the bone microenvironment Aim 3: Determine paracrine effects of AM on bone cell function & angiogenesis Our goal is to test the physiological importance of AM secreted by cancer cells in vivo and to validate it as a target for therapeutic intervention aimed at breaking the vicious cycle of prostate cancer metastases to bone.

描述（由申请人提供）：肾上腺髓质素[AM]是一种由前列腺癌分泌的多肽，是骨形成和成骨细胞增殖的有效刺激剂。它还对肿瘤细胞具有促血管生成和抗凋亡作用，因此在骨转移中具有自分泌和旁分泌作用。我们认为，来自前列腺癌细胞的AM通过以下方式促进骨转移的恶性循环：1)旁分泌刺激成骨细胞增殖和肿瘤血管生成，2)对肿瘤细胞的自分泌作用。我们认为，骨中的生长因子可以增加前列腺癌产生的AM，骨是固定生长因子的主要储存位点：这些因子通过破骨细胞骨吸收释放，也由成骨细胞合成。这两个过程都会因转移性肿瘤细胞而增加。骨源性因子刺激肿瘤细胞生长，并产生更多刺激成骨细胞和骨吸收的因子，导致骨转移的恶性循环特征。骨吸收的双膦酸盐抑制剂可以减少骨因子向微环境的释放。我们的初步数据支持 AM 在骨转移中的作用： 1) 在小鼠颅骨测定中，AM 是新骨形成的有效刺激剂； 2) AM功能丧失会减少肺癌模型中的骨转移； 3）过度表达AM的前列腺癌细胞加速了骨转移并表现出成骨细胞反应。我们提出四个假设： a) 肾上腺髓质素会增加前列腺癌骨转移 b) 骨转移瘤与软组织转移瘤中的肿瘤 AM 增加 c) AM对前列腺癌细胞具有自分泌生长和旁分泌血管生成作用 d) 肿瘤分泌的 AM 通过增加成骨细胞增殖来刺激骨骼我们建议通过三个具体目标来检验这些假设：目标 1：确定肿瘤肾上腺髓质素对骨转移的影响目标 2：确定骨微环境引起的 AM 表达变化目标 3：确定 AM 对骨细胞功能和血管生成的旁分泌作用我们的目标是测试体内癌细胞分泌的 AM 的生理重要性，并验证其作为治疗干预的目标，旨在打破前列腺癌骨转移的恶性循环。