Osteoblastic Factors in Prostate Cancer Bone Metastasis

Abstract

Purpose of review: Prostate cancer bone metastasis is the lethal progression of the disease. The disease frequently presents with osteoblastic lesions in bone. The tumor-induced bone can cause complications that significantly hamper the quality of life of patients. A better understanding of how prostate cancer induces aberrant bone formation and how the aberrant bone affects the progression and treatment of the disease may improve the therapies for this disease.

Recent findings: Prostate cancer-induced bone was shown to enhance tumor growth and confer therapeutic resistance in bone metastasis. Clinically, Radium-223, an alpha emitter that selectively targets bone, was shown to improve overall survival in patients, supporting a role of tumor-induced bone in prostate cancer progression in bone. Recently, it was discovered that PCa-induced aberrant bone formation is due, in part, from tumor-associated endothelial cells that were converted into osteoblasts through endothelial-to-osteoblast (EC-to-OSB) conversion by tumor-secreted BMP4. The unique bone-forming phenotype of prostate cancer bone metastasis plays a role in prostate cancer progression in bone and therapy resistance. Therapies that incorporate targeting the tumor-induced osteoblasts or EC-to-OSB conversion mechanism may reduce tumor-induced bone formation and improve therapy outcomes.

Keywords: Bone metastasis; EC-to-OSB conversion; Osteocrines; Prostate cancer; Tumor-induced bone.

Figure 1.. Therapy resistance from prostate tumor-induced bone.

PCa cells secrete factors that increase new bone formation. Osteoblasts in the new bone produce factors (osteocrines). Some of the osteocrines activate integrin signaling in PCa cells, resulting in phosphorylation of FAK-Y397 and Talin-S425, which leads to therapy resistance. Inhibition of FAK activity decreases therapy resistance. This figure was reprinted from Lee et al with permission from American Association of Cancer Research (23).

Figure 2.. Tumor-induced osteoblasts in the PCa bone lesions are derived from tumor- associated endothelial cells through EC-to-OSB transition.

PCa cells secrete factors, e.g. BMP4, which induce endothelial cells to transition into osteoblasts. The EC-to-OSB conversion is one of the mechanisms for the characteristic osteoblastic bone lesion of PCa. This figure was reprinted from Lin et al with permission from Developmental Cell (40).