Expression of Autotaxin and Lysophosphatidic Acid Receptors Increases Mammary Tumorigenesis, Invasion, and Metastases

Liu, Shuying; Umezu-Goto, Makiko; Murph, Mandi M.; Lu, Yiling; Liu, Wenbin; Zhang, Fan; Yu, Shuangxing; Stephens, L. Clifton; Cui, Xiaojiang; Murrow, George; Coombes, Kevin R.; Muller, William J.; Hung, Mien‐Chie; Perou, Charles M.; Lee, Adrian V.; Fang, Xianjun; Mills, Gordon B.

doi:10.1016/j.ccr.2009.03.027

Cited by 343 publications

(325 citation statements)

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“…Mouse model studies have revealed an important role for the ATX-LPA receptor axis in tumor progression as well as in other pathologies, ranging from inflammation to fibrosis (2,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Accordingly, pharmacological inhibition of ATX is an attractive way to interfere with LPA signaling for therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

“…Forced overexpression of ATX or individual LPA receptors promotes tumor progression in mouse models (13)(14)(15)(16), while LPA receptor deficiency protects from colon carcinogenesis (17). In addition to its role in cancer, ATX-LPA signaling has been implicated in lymphocyte homing and (chronic) inflammation (18), fibrotic diseases (19 and 20), and thrombosis (21).…”

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confidence: 99%

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Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Albers

Dong

Meeteren

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

208

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Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/ phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC 50 ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.A utotaxin (ATX or NPP2) is a secreted nucleotide pyrophosphatase/phosphodiesterase (NPP) originally isolated as an autocrine motility factor from melanoma cells (1). ATX, a ∼120 kDa glycoprotein, is unique amongst the NPPs in that it functions as a lysophospholipase D (lysoPLD) that converts extracellular lysophosphatidylcholine (LPC) into the lipid mediator lysophosphatidic acid (LPA; mono-acyl-sn-glycero-3-phosphate) (2-5). LPA acts on specific G protein-coupled receptors and thereby stimulates the migration, proliferation, and survival of many cell types (6 and 7) (Fig. 1). ATX is produced by various tissues and is the major LPA-producing enzyme in the circulation. Newly produced LPA is subject to degradation by membranebound lipid phosphate phosphatases (LPPs) (8 and 9). However, little is known about the dynamic regulation of steady-state LPA levels in vivo.ATX is essential for vascular development (10 and 11) and is found overexpressed in various human cancers (12). Forced overexpression of ATX or individual LPA receptors promotes tumor progression in mouse models (13-16), while LPA receptor deficiency protects from colon carcinogenesis (17). In addition to its role in cancer, ATX-LPA signaling has been implicated in lymphocyte homing and (chronic) inflammation (18), fibrotic diseases (19 and 20), and thrombosis (21). Therefore, the ATX-LPA axis qualifies as an attractive target for therapies.Potent and selective ATX inhibitors are now needed as a starting point for the development of targeted anti-ATX/LPA therapy. Direct targeting of LPA receptors seems to be a less attractive strategy, since LPA acts on multiple receptors that show overlapping activities (2 and 6). Since the initial finding that ATX is subject to product inhibition by LPA and sphingosine 1-phosphate (S1P) (22), various synthetic phospho-and phosphonate lipids have been explored as ATX inhibitors (23-26). However, s...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Albers

Dong

Meeteren

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

208

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“…Furthermore, LPA induced migration in breast cancer cells by activating LPA1, which promoted the phosphorylation of nonmuscle myosin II (NM II) light chain through the activation of ROCK and RhoA activity [18] . In addition, the expression of LPA1, LPA2, and LPA3 in mammary epithelium of transgenic mice induced a high frequency of late-onset, estrogen receptor (ER)-positive, invasive and metastatic mammary cancer [19] . LPA stimulated also tumorigenesis and metastasis in ovarian malignancy [20] .…”

Section: Gpcrs Activated By Bio-active Lipidsmentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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“…LPA levels as high as 10 μmol/L have been reported in ascites fluid of advanced ovarian cancer patients [5] . Mice that overexpress ATX in mammary epithelium develop spontaneous metastatic mammary tumors [72] . Further, the ATX gene is among the top 40 most upregulated genes in metastatic cancers [73] .…”

Section: Overview Of the Atx-lpa-lpp Axis Atx -The Predominant Producmentioning

confidence: 99%

“…Like for ATX, mice that overexpress LPA 1 , LPA 2 or LPA 3 in mammary epithelium develop spontaneous metastatic mammary tumors [72] . LPA 1 and/or LPA 2 receptors are overexpressed in many cancers, particularly gastric, ovarian, breast, colorectal and thyroid cancers compared to healthy tissues [99][100][101][102][103][104] .…”

Section: Lpa Receptor Diversity and Signalingmentioning

confidence: 99%

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

2016

J Biomed Res

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Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

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Expression of Autotaxin and Lysophosphatidic Acid Receptors Increases Mammary Tumorigenesis, Invasion, and Metastases

Cited by 343 publications

References 62 publications

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

GPCRs and cancer

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

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