PROSTATE CANCER BONE METASTASES: ROLE OF ADRENOMEDULLIN

描述（由申请人提供）：肾上腺髓质素[AM]是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物。它还能促进肿瘤细胞的血管生成和抗凋亡，因此在骨转移中具有自分泌和旁分泌作用。我们认为，前列腺癌细胞的AM通过旁分泌刺激成骨细胞增殖和肿瘤血管生成，以及自分泌对肿瘤细胞的影响，参与骨转移的恶性循环。我们认为骨中的生长因子增加了前列腺癌AM的产生，骨是固定生长因子的主要储存部位：这些生长因子通过破骨细胞骨吸收释放，也由成骨细胞合成。转移性肿瘤细胞增加了这两个过程。骨源性因子刺激肿瘤细胞生长，同时产生更多刺激成骨细胞和骨吸收的因子，形成骨转移的恶性循环特征。双膦酸盐骨吸收抑制剂可以减少骨向微环境中释放因子。我们的初步数据支持AM在骨转移中的作用：

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.