Key Points• ATX stored in a-granules of resting platelets is secreted upon tumor cell-induced aggregation leading to prometastatic LPA production.• Nontumoral ATX promotes early bone colonization by breast cancer cells and contributes to the progression of skeletal metastases.Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in a-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA.

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.

Experimental work was undertaken to evaluate whether intrahepatic recurrences, observed after resection of colorectal liver metastases in humans, could be due to the activation of dormant cancer cells already present within the liver at liver resection. About 250 cell aggregates (DHDK12 colon carcinoma cell line) were injected into the portal vein of 70 BD IX rats. Eight weeks later, 43 rats with no apparent liver metastases were divided randomly into three groups: group 1 (n = 15) served as control; group 2 (n = 15) were given cyclosporin A (10 mg kg body-weight-1 day-1) for 28 days; and group 3 (n = 13) underwent a 70 per cent hepatectomy. Twelve weeks after the injection of cells, when the animals were killed, 20 per cent of rats in group 1 had liver metastases, 80 per cent in group 2 (P less than 0.01) and 62 per cent in group 3 (P less than 0.05). Undetectable liver micrometastases may have been present at 8 weeks and had not developed until stimulation by cyclosporin A-induced immunosuppression or by liver regeneration after hepatectomy. A similar mechanism may occur clinically and explain some of the recurrences observed after resection of liver metastases.