Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts.

BACKGROUND: Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive 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 FINDINGS: Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to immunodeficiency 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/SIGNIFICANCE: Expression 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.

Plasminogen activator inhibitor type 1 is the most significant of the usual tissue prognostic factors in node-negative breast ductal adenocarcinoma independent of urokinase-type plasminogen activator.

PURPOSE: The aim of the present investigation was to evaluate the prognostic significance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) tissue contents in primary breast adenocarcinoma. PATIENTS AND METHODS: Patients from 3 medical centers were included between 1994 and 2001. Biologic factors in tumor extracts were all assayed in the same laboratory. PAI-1 and uPA were treated as continuous or dichotomized variables. Metastasis-free survival analyses were performed using the Cox model and the classification algorithm and regression tree (CART) in the whole population and in the subsets of node-negative (pN0) or positive (pN+) cases. Kaplan curves of metastasis-free survival were designed for different groups in relation to uPA/PAI-1 combinations. Urokinase-type plasminogen activator tumor level appears related to the anatomic degree of extension; conversely, PAI-1 tumor content is independent of tumor size and nodal extension. RESULTS: In univariate analysis, adjusted on usual prognostic factors, the metastasis risk increased with PAI-1 level in all patients (HR [hazard ratio], 3.1; P < .001), in pN0 (HR, 4.3; P < .001), and pN+ patients (HR, 2.3; P = .019). It increased also with uPA in all patients (HR, 2.6; P = 0.006). In multivariate analysis, when both variables were included, PAI-1 remained significant in all patients (HR, 2.4; P = .002) and pN0 patients (HR, 3.2; P = .003) but not uPA. CART analyses confirmed that the best partitioning factor was PAI-1. CONCLUSION: There was no evidence for any additional impact of uPA. PAI-1 is an independent prognostic factor in particular in pN0 breast ductal carcinoma.

[To be cured of breast cancer]. / Guérie d'un cancer du sein.

Can we say the magic word "cured", "cancer free" for breast cancer patients or can we say only survivors? This litterature review was focused on what mean cured of breast cancer with the long term effects on quality of life of locoregional and systemic therapies and the role of breast reconstruction. Finally changes in the intimacy, sex and love live and psychosocial live were stressed.