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Androgen ablation therapy is the first-line therapy in metastatic prostate cancer. It initially offers an objective clinical response, but eventually is stalled by the ominous development of refractoriness to hormonal therapy (stage D3). This ominous event signifies poor prognosis, uncontrolled tumor growth and curtailed survival to a median of only 10 months (1). Salvage chemotherapy does not improve the overall survival of stage D3 patients (2,3). The bone is the most prevalent site for metastases of prostate cancer (4). These lesions are associated with a potent local osteoblastic reaction, in contrast to the overwhelming majority of other solid tumors, whose bony metastases are generally associated with osteolysis (5,6). Osteoblastic metastases almost always represent the first and, frequently, the exclusive site of disease progression to stage D3 (3,7–9). The number of skeletal metastatic foci is the most powerful independent prognostic factor associated with limited response to hormone ablation therapy and poor survival of advanced prostate cancer (7–9). Disease progression to hormone-refractoriness frequently occurs only in the osteoblastic metastases, even though hormonal therapy may still provide adequate and sustained control of disease at the primary site (7–12). Consequently, the bone may not be just a passive, innocent bystander that suffers the consequences of metastatic tumor growth, but it may constitute the favorable microenvironment for the homing of metastatic prostate cancer cells (13–15). This may be secondary to interactions of prostate cancer cells with osteoblasts, to promote both the growth of metastatic prostate cancer cells and the osteoblastic reaction (13–17). Recently, bone-derived growth factors were reported to protect metastatic prostate cancer cells from chemotherapy-induced apoptosis, introducing the novel concept of bone-derived survival factors (18–20). We reviewed the current knowledge on osteoblast-derived survival factors, their relationship with local factors, such as the insulin-like growth factor I (IGF-I) and urokinase-type plasminogen activator (uPA) bioregulation system. These factors are implicated in the osteoblastic reaction and the benchto-bedside development of an anti-survival factor therapy, which has provided encouraging preliminary data in a phase II clinical trial with terminally ill, hormone-refractory and chemotherapy-resistant prostate cancer patients.

molecular medicine

Insulin-like Growth Factor I and Urokinase-type Plasminogen Activator Bioregulation System as a Survival Mechanism of Prostate Cancer Cells in Osteoblastic Metastases: Development of Anti-Survival Factor Therapy for Hormone-Refractory Prostate Cancer