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    • br Research perspective In vitro and in vivo

    2023-10-24


    Research perspective In vitro and in vivo studies have demonstrated that increased LPA/ATX signaling contributes to cancer initiation and progression. Recent findings on the role of non-tumoral ATX in cancer progression and metastasis highlighted a new functional contribution for the microenvironment onto primary tumor and cancer cell behaviors. From a clinical perspective, these results suggest that targeting both tumoral and non-tumoral ATX is required for having maximum therapeutic benefits. However, targeting both ATX compartments might potentially impact on current drug efficacy that would imply refining drug design and/or drug delivery for preventing tumor growth and metastasis dissemination. In addition, assessing drug efficacy in the clinic is a general high-reaching achievement, but that may become much more challenging in the context of LPA biology because complex pathways involve several distinct G protein-coupled receptors, inflammatory cytokine pathways, and transactivation of receptor tyrosine kinase signaling through metalloproteinase activations that drive ATX/LPA receptor axis in cancer. Therefore, efforts should be made on defining specific biomarkers linked to specific LPA receptor activities that would ensure both clinical validation of anti-LPA treatments and follow up disease progression/remission of patients receiving directed therapies [68].
    Acknowledgments The authors thank C. Kan for copy editing of the manuscript. This work was supported by grants from the INSERM, the University of Lyon (OP), the Comité Départemental de la Loire de la Ligue Contre le Cancer (OP) and the French Association pour la Recherche sur le Cancer, ARC (OP). RL was a recipient of a fellowship from the Ligue Nationale contre le Cancer.
    Introduction Autotaxin (ATX), or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), belongs to the ENPP family of ecto- and exo-enzymes, consisting of seven members and originally defined by their ability to hydrolyze nucleotides in vitro[1]. ATX is a secreted glycoprotein that was initially isolated as an autocrine motility factor for melanoma nitric oxide synthase inhibitors [2], and later found to promote metastasis and tumor vascularization in xenografted mice and an angiogenic response in Matrigel plug assays [3], [4], [5]. This suggested that ATX may contribute to tumor progression by providing an invasive and/or angiogenic microenvironment for both malignant and stromal cells. However, the biochemical activity of ATX has remained elusive for almost a decade, until it was discovered that ATX is identical to plasma lysophospholipase D (lysoPLD), the long-sought plasma enzyme that converts extracellular lysophosphatidylcholine into bioactive lysophosphatidic acid (LPA) [6], [7]. LPA stimulates proliferation, migration, survival and other cellular functions by acting on specific G protein-coupled receptors (GPCRs) that are linked to multiple G protein-effector pathways [8], [9], eventually leading to altered gene expression [10]. However, anti-migratory responses to LPA have also been reported [11], pointing to an increasing complexity of LPA receptor signaling. Six distinct GPCRs for LPA, termed LPA1–6 (or LPAR1–6), have been identified and validated until now. LPA1–3 belong to the so-called Edg receptor family (together with five receptors for sphingosine 1-phosphate [12], [13]), while LPA4–6 stand apart and are more closely related to the purinergic GPCRs [12], [13], [14], [15]. It thus appears that LPA receptors have evolved from distinct ancestor genes. LPA receptors are widely expressed and show both overlapping and distinct signaling properties and tissue distributions [12], [14]. ATX is synthesized as a pre-pro-enzyme. Following removal of its N-terminal signal peptide, ATX is further cleaved by proprotein convertases and then secreted as an active lysoPLD into the extracellular environment [16], [17], [18] (Fig. 1). Mature ATX consists of two N-terminal somatomedin B-like (SMB) domains, a central catalytic phosphodiester domain (PDE) and a C-terminal nuclease-like (NUC) domain. Structural studies have recently begun to shed light on the inner workings of ATX [19], [20]. The PDE domain has a well-defined lipid binding pocket and a nearby open tunnel that might serve as a lysophospholipid entry or/and exit channel [21]. The NUC domain serves to maintain the rigidity of the PDE domain, while the SMB domains mediate binding of ATX to activated integrins [19]. Integrin binding localizes ATX to the cell surface and thus provides a mechanism to generate and deliver LPA close to its cognate receptors [21], [22], [23]. Precisely how ATX activity is regulated and how the LPA product is released are questions that remain to be addressed. Importantly, the other ENPP family members lack intrinsic lysoPLD activity despite the similarity between their catalytic domains. Thus, ATX/ENPP2 is a unique lysoPLD with no functional redundancy within the ENPP family. Other LPA-generating ecto/exo-phosphoplipases include a phosphatidic acid (PA)-specific phospholipase A1 [24] and toxic sphingomyelinases D [25] (reviewed in [13]).