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Vascular Endothelial Growth Factor Contributes to Prostate Cancer–Mediated Osteoblastic Activity

¹ Department of Urology, School of Medicine, and ² Department of Cariology, School of Dentistry, University of Michigan, Ann Arbor, Michigan; ³ Department of Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and ⁴ Department of Immunology, Tianjin Medical University, Tianjin, China

Requests for reprints: Evan T. Keller, Room 5304 CCGCB Box 0940, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0940. Phone: 734-615-0280; Fax: 734-936-9220; E-mail: etkeller{at}umich.edu.

Prostate cancer frequently metastasizes to bone resulting in the formation of osteoblastic metastases through unknown mechanisms. Vascular endothelial growth factor (VEGF) has been shown recently to promote osteoblast activity. Accordingly, we tested if VEGF contributes to the ability of prostate cancer to induce osteoblast activity. PC-3, LNCaP, and C4-2B prostate cancer cell lines expressed both VEGF-165 and VEGF-189 mRNA isoforms and VEGF protein. Prostate cancer cells expressed the mRNA for VEGF receptor (VEGFR) neuropilin-1 but not the VEGFRs Flt-1 or KDR. In contrast, mouse pre-osteoblastic cells (MC3T3-E1) expressed Flt-1 and neuropilin-1 mRNA but not KDR. PTK787, a VEGFR tyrosine kinase inhibitor, inhibited the proliferation of human microvascular endothelial cells but not prostate cancer proliferation in vitro. C4-2B conditioned medium induced osteoblast differentiation as measured by production of alkaline phosphatase and osteocalcin and mineralization of MC3T3-E1. PTK787 blocked the C4-2B conditioned medium–induced osteoblastic activity. VEGF directly induced alkaline phosphatase and osteocalcin but not mineralization of MC3T3-E1. These results suggest that VEGF induces initial differentiation of osteoblasts but requires other factors, present in C4-2B, to induce mineralization. To determine if VEGF influences the ability of prostate cancer to develop osteoblastic lesions, we injected C4-2B cells into the tibia of mice and, after the tumors grew for 6 weeks, administered PTK787 for 4 weeks. PTK787 decreased both intratibial tumor burden and C4-2B–induced osteoblastic activity as measured by bone mineral density and serum osteocalcin. These results show that VEGF contributes to prostate cancer–induced osteoblastic activity in vivo.

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