Abstract 5061: Roles for matrix metalloproteinase-3 (MMP-3) in the prostate tumor-bone microenvironment.

Abstract

Abstract Prostate cancer commonly metastasizes to bone, resulting in lesions hallmarked by a mixture of osteolysis and osteogenesis. The “vicious cycle” is the paradigm describing tumor-bone interaction, and MMPs have been implicated in regulating the bioavailability and activity of growth factors that control the cycle. We have found that MMP-3, also known as stromelysin-1 and typically generated by host/stromal cells, is differentially expressed in the prostate tumor-bone microenvironment. Based on our initial observations, we hypothesize that host derived MMP-3 expression contributes to prostate tumor growth in bone. Using an in vivo intratibial model of prostate to bone metastases (PaIII), we found that that tumor growth and tumor induced bone remodeling were significantly mitigated (p<0.05) in MMP-3 null animals compared to wild type controls. Using a candidate approach to examine potential mechanisms, we focused on parathyroid hormone related protein (PTHrP), a powerful regulator of osteoblast behavior in the vicious cycle. We identified that MMP-3 processes mature PTHrP1-36 to yield PTHrP1-16, PTHrP17-26, and PTHrP27-36 fragments in vitro. The fragments did not impact osteoblast proliferation (MTT assay) or differentiation (Alizarin red staining), however, we observed a significant increase in migration of osteoblasts and osteoblast precursors in response to 10nM PTHrP1-16. The stimulation of migration by PTHrP1-16 was significantly greater than that induced by mature PTHrP1-36. Further analysis via confocal microscopy revealed a reduction in actin stress fibers as well as variations in lamellipodia and vinculin organization of osteoblasts treated with PTHrP1-16. In addition, western blots show a reduction of myosin light chain phosphorylation suggesting that PTHrP1-16 may mediate osteoblast migration by modulating Rho-associated protein kinase (ROCK) activity. Our data demonstrate that host MMP-3 contributes to prostate tumor growth and tumor induced changes in bone remodeling in vivo. Further, we have identified that mature PTHrP1-36 is subject to cleavage by MMP-3 resulting in PTHrP1-16, PTHrP17-26, and PTHrP27-36 fragments of which PTHrP1-16 significantly stimulates migration of osteoblasts and osteoblast precursors. Collectively, these data indicate that specific inhibition of MMP-3 and/or targeting MMP generated neo-epitopes would be efficacious for the treatment of prostate to bone metastases. Citation Format: Jeremy S. Frieling, Lizzie Atomi Pamen, Leah M. Cook, Shengyu Yang, Conor C. Lynch. Roles for matrix metalloproteinase-3 (MMP-3) in the prostate tumor-bone microenvironment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5061. doi:10.1158/1538-7445.AM2013-5061