The Bone Microenvironment in Prostate Cancer Metastasis

The propensity of prostate cancer cells to seed the skeleton and then progress into clinically relevant metastatic tumors is widely recognized and a major cause of morbidity and mortality for patients. The natural history of prostate adenocarcinoma most frequently begins with a tumor diagnosed at a localized stage, which is successfully treated by surgical and/or radiation therapy modalities. A relevant percentage of patients are clinically cured but approximately 20–30% will develop biochemical signs of recurrence, which respond to the inhibition of androgen receptor (AR) signaling by hormone-deprivation and receptor antagonists, before the inevitable transition into castration-resistant prostate cancer (CRPC). This stage simultaneously presents with or is rapidly followed by secondary tumors, which involve the skeleton in more than 90% of cases (mCRPC). While generalization in clinical practice is always unwise, it is indisputable that bone-metastatic prostate cancer is virtually incurable. Decades of research have revealed that the tissue microenvironment provided by the bone marrow is as important as the cell-autonomous features of tumor cells in fostering the right conditions that lead to establishment and progression of metastatic tumors in the skeleton.