Cancer Cell Expression of Autotaxin Controls Bone Metastasis Formation in Mouse through Lysophosphatidic Acid-Dependent Activation of Osteoclasts

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.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.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

[Lysophosphatidic acid: a "bioactive" phospholipid]

Lysophosphatidic acid (LPA) is a "bioactive" phospholipid able to generate growth factor-like activities in a wide variety of normal and malignant cell types. LPA is proposed to play an important role in normal physiological situations such as wound healing, vascular tone, vascular integrity, or reproduction. In parallel, LPA could also be involved in the etiology of some diseases such as atherosclerosis, cancer, or obesity. The bioactivity of LPA is mediated by the activation of specific G-protein coupled receptors (LPA1, LPA2, and LPA3) leading to the activation of a number of intracellular effectors. LPA is present in solution (bound to albumin) in various extracellular fluids (blood, ascites, aqueous humor), and is released in vitro by some cell types such as platelets, cancer cells, or adipocytes. LPA is a rather polar phospholipid, which cannot easily diffuse throughout plasma membrane, and its presence outside the cells requires soluble phospholipases (secreted phospholipase A2 and soluble lysophospholipase D/autotaxin), which synthesize LPA directly in the extracellular milieu, from precursors such as phosphatidic acid and lysophosphatidylcholine. In the future, LPA receptors, as well as the enzymes involved in LPA metabolism, will constitute promising pharmacological and transgenic targets to determine the physiopathological relevance of "bioactive" LPA in vivo

L’acide lysophosphatidique : un phospholipide « bioactif »

L’acide lysophosphatidique (LPA) est un phospholipide. Intermédiaire métabolique de synthèse des glycérolipides, le LPA peut se retrouver en solution (lié à l’albumine) dans divers liquides biologiques (sang, liquide d’ascite, humeurs) où il se comporte comme un puissant médiateur biologique au même titre que d’autres lipides comme les eicosanoïdes, le platelet activating factor ou la sphingosine-1-phosphate. L’objectif de cet article est de faire un bilan des connaissances actuelles sur le métabolisme (synthèse, dégradation), les mécanismes d’action (récepteurs, effecteurs intracellulaires) et les possibles implications physiopathologiques (cardiovasculaires, cancer, reproduction, obésité) du LPA que nous appellerons « bioactif » pour le distinguer du LPA « structural » impliqué dans la formation des membranes cellulaires et la synthèse des lipides neutres

Contrôle paracrine du développement du tissu adipeux par l'autotaxine et l'acide lysophosphatidique

Dans l'obésité, l'hypertrophie adipocytaire s'accompagne souvent du recrutement de nouveaux adipocytes, ou adipogenèse. Cet événement cellulaire est sous la dépendance d'hormones et de facteurs sécrétés au sein même du tissu adipeux. Parmi les lipides produits dans le compartiment extracellulaire des adipocytes, notre groupe a montré la présence d'acide lysophosphatidique (LPA). Le LPA est un phospholipide bioactif capable de réguler plusieurs réponses cellulaires via l'activation de récepteurs membranaires spécifiques couplés aux protéines G. Nous avons montré que le LPA, via l'activation du récepteur LPA1, augmentait la prolifération des préadipocytes et inhibait l'adipogenèse. La synthèse extracellulaire de LPA est catalysée par une lysophospholipase D sécrétée par l'adipocyte : l'autotaxine (ATX). L'expression de l'ATX adipocytaire augmente au cours de l'adipogenèse ainsi que dans le tissu adipeux d'individus présentant un diabète de type 2 associé à une obésité massive. Un rôle du LPA et de l'ATX comme régulateurs paracrines de l'adipogenèse et/ou du diabète associé à l'obésité est donc envisagé

[Secretion and role of autotaxin and lysophosphatidic acid in adipose tissue]

International audienceIn obesity, adipocyte hypertrophy is often associated with recrutement of new fat cells (adipogenesis) under the control of circulating and local regulatory factors. Among the different lipids released in the extracellular compartment of adipocytes, our group found the presence of lysophosphatidic acid (LPA). LPA is a bioactive phospholipid able to regulate several cell responses via the activation of specific G-protein coupled membrane receptors. Our group found that LPA increases preadipocyte proliferation and inhibits adipogenesis via the activation of LPA1 receptor subtype. Extracellular LPA-synthesis is catalyzed by a lysophospholipase D secreted by adipocytes: autotaxin (ATX). Adipocyte ATX expression strongly increases with adipogenesis as well as in individuals exhibiting type 2 diabetes associated with massive obesity. A possible contribution of ATX and LPA as paracrine regulators of adipogenesis and obesity associated diabetes is proposed

Etude de la réceptivité adrénergique et de la production d'acide lysophosphatidique par le tissu adipeux humain

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Les sécrétions du tissu adipeux (rôles de l'autotaxine et recherche de nouvelles adipokines)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Etude de la régulation et du rôle de l'autotaxine et de l'acide lysophosphatidique dans le tissu adipeux et le rein

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF