PROSTATE CANCER BONE METASTASES: ROLE OF ADRENOMEDULLIN

描述(申请人提供)：肾上腺髓质素(AM)是前列腺癌分泌的一种多肽，是骨形成和成骨细胞增殖的有力刺激因子。它对肿瘤细胞也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通过以下两种方式参与骨转移的恶性循环：1)旁分泌刺激成骨细胞增殖和肿瘤血管生成；2)自分泌作用于肿瘤细胞。我们认为前列腺癌AM的产生是由骨中的生长因子增加的，骨中的生长因子是固定化生长因子的主要储存部位：这些生长因子由破骨细胞性骨吸收释放，也由成骨细胞合成。这两个过程都被转移的肿瘤细胞增加。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。骨吸收的双膦酸类抑制剂可以减少从骨骼向微环境释放的因子。我们的初步数据支持AM在骨转移中的作用： 1)在小鼠颅骨实验中，AM是一种有效的新骨形成刺激因子；2)AM功能的丧失减少了肺癌模型中的骨转移；以及3)过表达AM的前列腺癌细胞加速了骨转移并表现出成骨反应。我们提出四个假设： A)肾上腺髓质素增加前列腺癌骨转移 B)骨转移与软组织转移相比，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通过增加成骨细胞的增殖来刺激骨骼 我们建议用三个具体目标来检验这些假设： 目的1：确定肿瘤肾上腺髓质素对骨转移的影响 目的2：确定骨微环境对AM表达的影响 目的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，并验证其作为旨在打破前列腺癌转移到骨的恶性循环的治疗干预的靶点。

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.