Despite the clinical implication and high incidence of bone and spinal metastases, the molecular mechanisms behind prostate cancer metastasis to bone and spine are not well understood. In this review the molecular mechanisms that may contribute to the highly metastatic phenotype of prostate cancer are discussed. Proangiogenic factors such as vascular endothelial growth factor (VEGF) have been shown to not only aid in the metastatic capabilities of prostate cancer but also encourage the colonization and growth of prostate tumour cells in the skeleton. The importance of VEGF in the complex process of prostate cancer dissemination to the skeleton is discussed, including its role in the development of the bone premetastatic niche, metastatic tumour cell recognition of bone, and bone remodeling. The expression of VEGF has also been shown to be upregulated in prostate cancer and is associated with clinical stage, Gleason score, tumour stage, progression, metastasis, and survival. Due to the multifaceted effect VEGF has on tumour angiogenesis, tumour cell proliferation, and bone destruction, therapies targeting the VEGF pathways have shown promising clinical application and are being investigated in clinical trials. 1. Introduction The five-year survival rate for prostate cancer is extremely high when confined to the prostate, but in the presence of metastatic disease it is reduced to 33% [1]. In Australia, prostate cancer contributes to almost 5% of all registered male deaths [2] of which more than 80% will have developed spinal metastases during the course of their disease [3–5]. Once cancer metastasizes to bone and the vertebral column, patients often experience intractable pain and neurological deficit due to pathological fractures, spinal instability, and metastatic epidural spinal cord compression. The neurological sequelae include sensory disturbance, motor weakness, paralysis, and incontinence, leading to decreased function, inability to ambulate and impaired quality of life [5]. Treatment options include radiotherapy, hormonal therapy, chemotherapeutic agents such as docetaxel, cabazitaxel, sipuleucel-T and abiraterone acetate, and decompression and stabilization surgery [6, 7]. These modalities may be able to extend survival rates but are all predominantly palliative, with median survival time limited from one to two years from the onset of metastases [5, 6]. Despite the clinical implication and high incidence of spinal metastasis, the molecular mechanisms behind prostate cancer metastasis to bone and the spine are not well understood. Vascular
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