PROSTATE CANCER BONE METASTASES: ROLE OF ADRENOMEDULLIN

前列腺癌骨转移：肾上腺髓质素的作用

• 批准号: 6918192
• 负责人: THERESA A GUISE
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/6918192
• 关键词: angiogenesis; angiogenesis factor; apoptosis; athymic mouse; autocrine; bone neoplasms; cell motility; cell proliferation; clinical research; human tissue; laboratory mouse; male; metastasis; neoplastic growth; osteoblasts; osteoclasts; paracrine; peptide hormone; prostate neoplasms; vasodilators

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）：肾上腺素蛋白[AM]是由前列腺癌和骨形成和成骨细胞增殖的有效刺激剂分泌的多肽。它还针对肿瘤细胞促血管生成和抗凋亡，因此在骨转移中具有自分泌和旁分泌作用。我们提出，来自前列腺癌细胞的AM通过：1）旁分泌刺激成骨细胞增殖和肿瘤血管生成，以及2）对肿瘤细胞的自分泌作用。我们建议，骨骼中的生长因子增加了前列腺癌的AM产生，这是固定生长因子的主要存储位点：这些储存位点是由整骨骨骨吸收释放的，也由成骨细胞合成。转移性肿瘤细胞增加了这两个过程。骨源性因素刺激肿瘤细胞生长，并产生更多刺激成骨细胞和骨吸收的因素，从而导致骨转移的恶性循环特征。通过双膦酸盐抑制剂的骨吸收抑制剂，可以降低骨骼从骨骼进入微环境的因子的释放。我们的初步数据支持AM在骨转移中的作用： 1）AM是小鼠钙钙测定法中新骨形成的有效刺激剂； 2）AM功能丧失减少肺癌模型中的骨转移； 3）前表达AM的前列腺癌细胞加速了骨转移，并显示成成骨细胞反应。我们提出了四个假设： a）肾上腺素蛋白增加前列腺癌骨转移 b）骨骼与软组织转移的肿瘤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 我们建议以三个特定目标检验这些假设： AIM 1：确定肿瘤肾上腺素对骨转移的影响 目标2：确定由骨微环境引起的AM表达的变化 AIM 3：确定AM对骨细胞功能和血管生成的旁分泌作用 我们的目标是测试癌细胞在体内分泌的AM的生理重要性，并将其验证为治疗干预措施的目标，目的是破坏前列腺癌转移对骨骼的恶性循环。