BackgroundBone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorbtive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2) is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD) activity, ATX controls the level of lysophosphatidic acid (LPA) in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models.Methodology/Principal FindingsIntravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to inmmunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis.Conclusion/SignificanceExpression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and osteoclast differentiation. Therefore, targeting the autotaxin/LPA track emerges as a potential new therapeutic approach to improve the outcome of patients with bone metastases.

Autotaxin (ATX, NPP-2) is a secreted protein with both an oncogenic action on mouse breast tissue and metastatic properties on breast cancer cells. Due to its lysophospholipase D activity, ATX generates lysophosphatidic acid (LPA) from lysophosphatidylcholine and controls LPA levels in the blood. We have recently showed that platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. However, how LPA is produced at the metastatic site and the role of ATX by cancer cells in this metastasis process are still unknown. Here, we found that in vitro, forced expression of ATX in human breast cancer MDA-B02 cells (MDA-B02/ATX) increased invasiness, proliferation and enhanced their pro-osteoclastic function. In vivo, intravenous injection of MDA-B02/ATX cells to inmmunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss and tumor burden, and higher active osteoclast number at the bone metastatic site. Mouse 4T1 breast cancer cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. We found that 4T1 cells expressed active ATX. In vitro, silencing ATX[O1] expression inhibited invasion but not proliferation of 4T1-siATX cells. In vivo, silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at bone the metastatic site. Altogether, these results demonstrated that expression of ATX by cancer cells controls bone metastasis formation and that targeting ATX in patients might contribute to the development of additional therapies against bone metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2368.

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