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

David, Marion; Wannecq, Estelle; Descôtes, Françoise; Jansen, Silvia; Deux, Blandine; Ribeiro, J. L.; Serre, Claire-Marie; Grès, Sandra; Bendriss‐Vermare, Nathalie; Bollen, Mathieu; Saez, S.; Aoki, Junken; Saulnier-Blache, Jean Sébastien; Clézardin, Philippe; Peyruchaud, Olivier

doi:10.1371/journal.pone.0009741

Cited by 106 publications

(129 citation statements)

References 51 publications

(86 reference statements)

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“…The LPA receptor (LPA 1 ) is reported to be expressed on 4T1.2 cells and to be involved in both in vitro and in vivo migration by these cells (David et al, 2010;Kim and Adelstein, 2011). The lysates were analyzed by western blot for the presence of phosphorylated Akt (S473).…”

Section: Resultsmentioning

confidence: 99%

Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

et al. 2011

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Phosphoinositide 3-kinase c (PI3Kc) consists of a catalytic subunit p110c, which forms mutually exclusive dimers with one of the regulatory subunits called p101 and p84/p87 PIKAP . Recently, PI3Kc emerged as being a potential oncogene because overexpression of the catalytic subunit p110c or the regulatory subunit p101 leads to oncogenic cellular transformation and malignancy. However, the contribution of the individual subunits to tumor growth and metastasis and the mechanisms involved are not understood. We therefore individually knocked down the PI3Kc subunits (p84, p101 and p110c) in MDA-MB-231 cells, which reduced in vitro migration of the cell lines. Knockdown of p110c or p101 inhibited apoptosis, Akt phosphorylation and lung colonization in SCID mice. Similarly, the knockdown of p110c and p101 in murine epithelial carcinoma 4T1.2 cells inhibited primary tumor growth and spontaneous metastasis, as well as lung colonization. In contrast, knockdown of p84 in MDA-MB-231 cells enhanced Akt phosphorylation and lung colonization. These findings are the first to implicate differential functions of the two PI3Kc regulatory subunits in the process of oncogenesis, and indicate that loss of p101 is sufficient to reduce in vivo tumor growth and metastasis to the same extent as that of p110c.

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Section: Resultsmentioning

confidence: 99%

Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

et al. 2011

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“…Previous studies have shown that stimulation with LPA induced osteoclast fusion and was required for formation of multinucleated osteoclasts (39). Therefore, it was suggested that LPA may also play a crucial role in osteoclast formation.…”

Section: Discussionmentioning

confidence: 98%

Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Miyabe

Iwai

et al. 2013

Arthritis & Rheumatism

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Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA 1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA 1 on the development of arthritis.Methods. Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA 1 on collageninduced arthritis (CIA) were evaluated using LPA 1 -deficient mice or LPA 1 antagonist. Migrating fluorescence-labeled CD11b؉ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4؉ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.Results. LPA 1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA 1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA 1 antagonist also ameliorated murine CIA. Abrogation of LPA 1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b؉ macrophages from LPA 1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA 1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA 1 deficiency or LPA 1 inhibition in vitro.Conclusion. Collectively, these results indicate that LPA/LPA 1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA 1 may be a promising target molecule for RA therapy.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammatory cell infiltration and bone destruction at multiple joints. The inflammation process in RA leads to synovial hyperplasia with proliferation of fibroblast-like synoviocytes (FLS), angiogenesis, and infiltration of inflammatory cells, including lymphocytes and macrophages (1,2).

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“…A number of studies have demonstrated that ATX activity promotes in vitro motogenic activity in ovarian ( 119,147 ), hepatocellular ( 148 ), breast, and melanoma cell lines ( 118 ), among others, while pharmacological and genetic inhibition of ATX decreases lung metastasis in a murine orthotopic model of breast cancer ( 103,149 ). Available evidence suggests that metastasis to bone can be promoted by ATX through multiple mechanisms, including regulation of osteoclast differentiation ( 103 ), interaction with integrin ␣ V ␤ 3 expressed on the surface of tumor cells ( 150 ), and bone resorption through the induction of IL6 and IL8 expression ( 151 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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

Cited by 106 publications

References 51 publications

Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

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