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Vascular Endothelial Growth Factor Contributes to the Prostate Cancer-Induced Osteoblast Differentiation Mediated by Bone Morphogenetic Protein

Departments of ¹ Pathology, School of Medicine, ² Cardiology, Restorative Sciences and Endodontics, and ³ Periodontics, Prevention and Geriatrics, School of Dentistry, University Michigan, Ann Arbor, Michigan; ⁴ Department of Immunology, Tianjin Medical University, Tianjin, China; ⁵ Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁶ Department of Urology, Kanazawa University, Japan

Human prostate cancer has a high predisposition to metastasize to bone, resulting in the formation of osteoblastic metastases. The mechanism through which prostate cancer cells promote osteoblastic lesions is undefined. Vascular endothelial growth factor (VEGF) has been implicated as a mediator of osteoblast activity. In the present study, we examined if prostate cancer cells promote osteoblastic activity through VEGF. We found that LNCaP and C4-2B prostate cancer cell lines and primary tumor and metastatic prostate cancer tissues from patients expressed VEGF. Bone morphogenetic proteins (BMPs), which are normally present in the bone environment, induced VEGF protein and mRNA expression in C4-2B cells. Furthermore, BMP-7 activated the VEGF promoter. Noggin, a BMP inhibitor, diminished VEGF protein expression and promoter activity in C4-2B cells. Conditioned media (CM) from C4-2B cells induced pro-osteoblastic activity (increased alkaline phosphatase, osteocalcin, and mineralization) in osteoblast cells. Both noggin alone and anti-VEGF antibody alone diminished C4-2B CM-induced pro-osteoblastic activity. Transfection of C4-2B cells with VEGF partially rescued the C4-2B CM-induced pro-osteoblastic activity from noggin inhibition. These observations indicate that BMPs promote osteosclerosis through VEGF in prostate cancer metastases. These results suggest a novel function for VEGF in skeletal metastases. Specifically, VEGF promotes osteoblastic lesion formation at prostate cancer bone metastatic sites.

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