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.
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