Mediators of Inflammation

Mediators of Inflammation / 2017 / Article

Review Article | Open Access

Volume 2017 |Article ID 9173090 | 15 pages | https://doi.org/10.1155/2017/9173090

Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development

Academic Editor: Santiago Partida-Sanchez
Received08 Sep 2017
Accepted22 Nov 2017
Published21 Dec 2017

Abstract

Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA1–6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer-related inflammation and its impact on cancer progression.

1. Introduction

Lysophosphatidic acid (LPA) consists of an acyl chain at the sn-1 (or sn-2) position of a glycerol backbone and a phosphate head group. It is the smallest (molecular weight: 430–480 Da) and the simplest bioactive glycerophospholipid derived from membrane phospholipids [1, 2]. Nevertheless, it is involved in a wide range of activities, from phospholipid synthesis to a number of physiological responses as a lipid mediator [3]. LPA activates at least six G-coupled protein receptors (LPA1–6) stimulating different signaling pathways through heterotrimeric G proteins such as Gi/0, G12/13, Gq/11, and Gs. The outcome of LPA signaling is dependent on cellular context and impacts on biological processes such as wound healing, differentiation, neurogenesis, and survival, to name a few [4]. Due to its small structure, LPA is water soluble and concentrations > 5 μM have been reported in serum; concentrations < 1 μM have been found in other biofluids such as plasma, saliva, follicular fluid, cerebrospinal fluid, and malignant effusions [57]. It is known that ATX-LPA signaling increases during wound healing, and both are produced and detected in blister fluids, where they mediate platelet aggregation and skin reepithelization [8]. During this process, ATX-LPA signaling induces production of proinflammatory cytokines. Therefore, aberrant activation of this axis promotes an inappropriate immune response that leads to a proinflammatory state in pathologies like cancer [9].

2. Lysophosphatidic Acid Synthesis and Metabolism

LPA is a membrane-derived lysophospholipid from phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE) [7]. Therefore, several species can be found, differing only in the length and saturation of the acyl or alkyl fatty acid chain [7, 10]. The most abundant plasma LPA species are 18:2 > 18:1 ≥ 18:0 > 16:0 > 20:4 with an acyl group [11, 12]. Although acyl-LPA 18:2 is the most numerous species, acyl-LPA 18:1 is the most frequently used in current research [13].

There are two major pathways for LPA production (Figure 1(a)). The main pathway is the cleavage of membrane phospholipids into lysophospholipids by the removal of a fatty acid chain by phospholipase A (PLA1 or PLA2). Subsequently, ATX cleaves the head group (choline, ethanolamine, or serine) on the lysophospholipids and turns them into LPA [14]. ATX (also known as ENPP2) is a 125 kDa-secreted enzyme from the family of ectonucleotide pyrophosphatases/phosphodiesterases (reviewed by [15]) located on Chr8q24 [16]. Among the seven members of this family, ATX is a unique enzyme that shows lysophospholipase D activity [17, 18]. This enzyme produces most of the extracellular LPA. Enpp2+/− mice and inhibitors targeting ATX decrease LPA plasma concentration by >50% [1922]. ATX generates LPA from plasma membrane phospholipids and from circulating lysophosphatidylcholine (LPC) bound to albumin [23]. ATX is essential for development since Enpp2−/− is lethal at embryonic day 9.5–10.5, with marked vascular and neural tube defects [20, 21]. ATX is also important in adipogenesis since it is upregulated during preadipocyte differentiation to adipocytes and secreted into circulation by the adipose tissue [24].

A second, less common, route of LPA production is the cleavage of phospholipids into phosphatidic acid (PA) by phospholipase D (PLD) at the cell surface. PA is then hydrolyzed in the outer leaflet of the plasma membrane by secreted PLA2 (sPLA2) releasing LPA to the microenvironment [15].

LPA turns over with a half-life of about 3 min in the circulation [25]. Therefore, its main effects are autocrine and paracrine when bound to albumin [10]. LPA turnover is regulated by ATX activity and LPA degradation by lipid phosphate phosphohydrolase type 1 (LPP1) which hydrolyze LPA into monoacylglycerol (MAG) in the outer leaflet of the cell membrane [26, 27] and LPA-acyltransferase (LPAAT), which transfer an acyl chain to LPA converting it into PA in the inner leaflet of the cell membrane [10]. Recently, a negative feedback loop has been described for the ATX-LPA axis [28]; in this mechanism, LPA signaling through its receptor LPA1/3 induces downregulation of ATX mRNA. Similarly, low levels of circulating LPA increase ATX mRNA, particularly in the adipose tissue of female Balb/c mice [28].

3. LPA Receptors

As previously mentioned, LPA signals through at least six G protein-coupled receptors LPA1–6 (Figure 1(b)): gene names are LPAR1-LPAR6 (human) and Lpar1-Lpar6 (mouse) [30, 31]. All LPA receptors are rhodopsin-like, with seven transmembrane domain receptors that range from 39 to 42 kDa and differ in their tissue distribution and downstream effectors [7]. According to their homology, there are two LPA receptor families: the endothelial differentiation gene (EDG) family and the non-EDG family [32, 33]. In addition to homology, they differ in their activation by different LPA species (Figure 2). Although acyl-LPA 18:2 is the most abundant species, the EDG family is more potently stimulated by acyl-LPA (LPA1/2), and LPA3 preferentially bounds to 2-acyl-LPA. The non-EGD family member LPA5 is more potently stimulated by alkyl-LPA and LPA6 by 2-acyl-LPA, specifically [33]. These differences show that a wide range of physiological effects is modulated through these receptors and LPA species in a context and cell type-dependent manner.

3.1. Endothelial Differentiation Gene Family

In 1996, LPA1 was the first receptor to be identified and it is the best studied to date. Hecht et al. [35] described a neuroblast cell line overexpressing the ventricular zone gene-1 receptor (Vgz-1), to which LPA binds specifically to induce cell rounding and activation of Gαi. Also known as EDG-2, Vgz-1 was later renamed LPA1. Right after its discovery, two other orphan receptors, LPA2 and LPA3, were identified based on their homology to LPA1 [3638].

LPA1 is a 41 kDa protein of 364 amino acids located in Chr9q31.3 and consists of at least 5 exons [30, 31]. This receptor couples with and activates 3 types of G protein, Gαi/0, Gαq/11, and Gα12/13, which initiate downstream signaling through PI3K/AKT, Rho, MAPK, and PLC (Figure 1(b)). These pathways are involved in several cellular processes, including cell proliferation and survival, adhesion, migration, AC inhibition, and Ca2+ mobilization [31, 39]. It is widely expressed in most tissues such as brain, uterus, testis, lung, small intestine, heart, stomach, kidney, spleen, thymus, and skeletal muscle at different developmental stages with a variable expression, particularly in the central nervous system (CNS) [36, 39], where, during development, LPA1 is found in the ventricular zone, superficial marginal zone, and meninges. After birth, LPA1 expression is reduced in the aforementioned areas and continues in oligodendrocytes, particularly during myelination, as well as in astrocytes, where it elicits a wide range of processes (reviewed by [40]). Targeted deletion of Lpar1−/− showed a 50% of perinatal lethality related to an impaired suckling behavior probably due to defective olfaction. Surviving mice showed craniofacial malformations and reduced body size [41]. Additionally, LPA1 has been closely related to the induction of neuropathic pain due to nerve injury via LPA1/RhoA/rock-mediated demyelination with a subsequent loss of the structural and functional integrity of neurons, as discussed elsewhere [42].

LPA2 receptor (EDG-4) has a ~50–60% homology to LPA1, with an estimated mass of 39 kDa and 348 amino acids [36]. Located on Chr19p12, it consists of 3 exons in both humans and mice [30, 39]. LPA2 couples to the same G proteins as LPA1 (Figure 1(b)): Gαi/0, Gαq/11, and Gα12/13 [36, 39]; therefore, it can similarly activate downstream signaling but, unlike LPA1, can also promote migration through the focal adhesion molecule TRIP6 [43, 44]. LPA2 activation is associated with survival and migration. Compared with LPA1, its expression is more diffuse during development, more restricted in adults, and with high expression in leukocytes and testis in humans and in kidney, uterus, and testis in mice [36, 39, 45]. LPA2 knockout mice are mostly normal, suggesting a possible functional redundancy in relation to LPA1. A Lpar1−/− and Lpar2−/− model has also been evaluated [46]. In this model, Lpar1−/− phenotype predominated with 50% perinatal lethality, cranial malformations, and reduced body size, but it also exhibited frontal hematomas [46].

LPA3 receptor (EDG-7) contains 3 exons, has 353 amino acids, and a 40 kDa-estimated mass [37, 38]. This receptor has 52% and 48% homology with LPA1 and LPA2, respectively, and is located on Chr1p22.3-p31.1 [30, 38, 39]. LPA3 couples to G proteins, Gαi/0 and Gα11/q (Figure 1(b)), and therefore mediates downstream activation of MAPK, PLC, and inactivation of AC [47]. It has been reported that this receptor is more potently activated by 2-acyl-LPA with unsaturated fatty acids [2]. In humans, LPA3 is expressed in heart, lung, pancreas, prostate, testis, ovaries, and brain [37]. In mice, it is expressed in testis, kidney, lung, intestine, and moderately, small intestine [39]. Functional deletion of LPA3 in female mice showed delayed and defective embryo implantation through the downregulation of cyclooxygenase-2 (COX-2) and reduced levels of prostaglandins, which are essential for this process [48]. In deficient LPA1–3 male mice, an independent of testosterone signaling reduced sperm count and mating activity was found [49]. This evidence suggests the role of LPA3 in reproductive functions.

3.2. Nonendothelial Differentiation Gene Family

In 2003, the first LPA receptors structurally distant from the EDG receptor family were described [50]. The orphan GPCR P2Y9/GPR23 has only 20–24% homology with LPA1–3, but it specifically binds to LPA. Its signaling promotes an increase in intracellular Ca2+ concentration and adenylyl cyclase activity in “LPA receptor-null” cells exogenously expressing P2Y9 [50]. Soon, LPA5 and LPA6 description followed [5155].

LPA4 (P2Y9/GPR23) is encoded by 1 exon containing 370 amino acids with a 42 kDa mass [30, 50, 56]. Located on ChrXq21.1, it was the first to be described that couples to four G proteins: Gαi/0, Gα11/q, Gα12/13, and Gαs (Figure 1(b)) [57]. LPA4 signaling promotes Rho-mediated neurite retraction and stresses fiber formation, Ca2+ mobilization, and regulation of cAMP concentration [57]. In humans, LPA4 expression is high in ovaries, moderated in thymus and pancreas, and low in brain, heart, small intestine, testis, prostate, colon, and spleen [13, 50]. In mice, it is expressed in heart, ovaries, thymus, skin, and developing brain [57, 58]. Lpar4 −/− mice showed no apparent abnormality, but there was a 30% lethality, probably due to blood vessel defects during embryogenesis [58, 59].

LPA5 (GPR92) is a 41 kDa protein consisting of 372 amino acids coded in an intronless open reading frame [51, 52]. This receptor is located on Chr12p13.31 and has a 35% homology with LPA4 [51, 52]. LPA5 couples to G proteins, Gα11/q and Gα12/13 (Figure 1(b)), by which Ca2+ mobilization, inositol phosphate production, neurite retraction, and stress fiber formation are mediated [51, 52]. It has been reported that LPA5 preferentially binds to alkyl-LPA (16:0), rather than acyl-LPA (18:1) [33]. LPA5 is found in heart, placenta, spleen, brain, lung, and gut in humans [51]. It is also highly expressed in the lymphocyte compartment of the gastrointestinal tract and platelets [51, 60]. In mice, it is found in the brain, heart, kidney, liver, lung, muscle, skin, spleen, stomach, small intestine, testis, and thymus [52]. Lpar5−/− mice have no apparent phenotypic defects but show a reduced pain sensitivity, faster recovery from inflammation, and reduction in social exploration [61, 62]. They also exhibit nocturnal hyperactivity and anxiety compared to Lpar5+/+ mice [61]. Null mice were also protected from developing neuropathic pain by a mechanism different from LPA1 [62].

LPA6 (P2Y5) is the most recently identified LPA receptor and the last accepted by the IUPHAR Nomenclature Committee in 2010 [31, 53, 54]. It is a 344-amino acid protein with an estimated mass of 39 kDa [30]. Regarding homology with LPA4 [50], it is the closest receptor and is located on Chr13q14 [30, 55]. LPA6 couples to Gαi/0 and Gα12/13 (Figure 1(b)), by which a decrease in cAMP, Rho-dependent morphological changes, Ca2+ mobilization, and MAPK activation are mediated [53, 54]. It has also been reported that LPA6 is preferentially activated by 2-acyl-LPA, rather than 1-acyl-LPA [53]. This receptor has been found in rats’ brain, heart, lung, kidney, pancreas, liver, stomach, and small and large intestine [54]. In humans, it has been related to hair growth since a mutation of LPAR6 was found in patients with hypotrichosis simplex, an alopecia-causing disorder [55].

3.3. EDG and Non-EDG Receptor Effects in Cancer

Extensive evidence demonstrate that the receptors from the EDG family promote tumor progression in a wide variety of cancers by enhancing proliferation, survival, migration, and invasion [7]. Conversely, evidence shows that members from the non-EDG family have the opposite effect.

Reconstitution of Lpar4 in mouse embryonic fibroblasts derived from Lpar4−/− mice reduces cell motility due to an LPA-induced decrease in Rac activation [58]. Also, LPA4 expression in colon cancer cells (DLD1 and HTC116) suppresses cell migration and invasion compared to null-LPA4 cells [58, 63]. Similarly, in rat sarcoma cells, overexpression of Lpar5 significantly reduced motility and suppressed MMP2 activation. On the other hand, Lpar5 knockdown induced the opposite effect [64]. In B16F10 mice melanoma cells, LPA5 reduced migration through a cAMP/PKA-dependent pathway and induced chemorepulsion instead of attraction via LPA [65]. Additionally, in colon cancer cells, lines DLD1, and HCT116, LPA6 expression significantly reduced cell growth and motility [63].

In rat lung adenocarcinoma, loss of LPA3 due to methylation of the promoter enhances tumor progression by increasing invasion, suggesting a protective role of LPA3 in this neoplasia [66]. By contrast, in human fibrosarcoma, LPA4 was shown to increase cAMP levels and subsequently activate Rac1 to induce invadopodia, a process directly correlated with invasion and metastasis [67]. Additionally, in rat lung carcinoma, LPA5 is highly expressed due to unmethylation of the promoter, and cells expressing only LPA5 showed enhanced proliferation, migration, and invasion [68]. Moreover, hepatocellular carcinoma (HCC) cells overexpressing LPA6 sustain an increase in tumor growth, migration, and invasion. Moreover, LPA6 expression was associated with a worse clinical outcome in these patients [69].

In brief, LPA receptors can have homologous and antagonistic effects depending on the tumor. Therefore, they should be studied in a cancer-specific context to better evaluate their role in tumor development and progression, as well as their potential therapeutic value.

Since the 19th century, an association between inflammation and cancer was proposed [70]. Inflammatory components are often present in most types of cancer, such as white blood cells, tumor-associated macrophages, and proinflammatory ILs [70, 71]. In several cases, inflammation can predispose individuals to certain types of cancer, including cervical, gastric, colon, hepatic, breast, lung, ovarian, prostate, and thyroid cancer [7281]. There is also evidence that the use of nonsteroidal anti-inflammatory drugs can reduce the risk of developing colon and breast cancer and reduce the related mortality, as discussed elsewhere [82, 83].

In general, two mechanisms have been proposed to link inflammation and cancer. In the intrinsic pathway, genetic events promoting development initiate the expression of inflammation-related circuits leading to an inflammatory microenvironment. Conversely, in the extrinsic pathway, inflammatory conditions facilitate cancer development. In both cases, a cancer-related inflammation (CRI) is induced and it is proposed as a tumor-enabling characteristic and the seventh hallmark of cancer [71]. CRI enables unlimited replicative potential, independence of growth factors, resistance to growth inhibition, escape of cell death, enhanced angiogenesis, tumor extravasation, and metastasis [84]. Therefore, understanding key components of inflammation is important for better therapeutics in cancer and other diseases.

The ATX-LPA axis is involved in wound healing response, where it induces platelet aggregation, lymphocyte homing, cytokine production, keratinocyte migration, proliferation, and differentiation under physiological conditions [85]. When acute inflammation becomes chronic in unpaired homeostasis, ATX-LPA signaling induces an augmented cytokine production and lymphocyte infiltration, aggravating the inflammation in conditions such as asthma, pulmonary fibrosis, and rheumatoid arthritis, to name a few [86]. In a cancer context, it also promotes cell survival, proliferation, migration, invasion, and angiogenesis, enhancing its progression in a state similar to a “wound that never heals” [84, 87].

4.1. Lung

ATX-LPA axis has been studied in airway inflammation where protein kinase C δ (PKCδ) mediates LPA-induced NFκB transcription and IL-8 secretion in human bronchial epithelial cells (HBEpCs) [88]; LPA activation of PKCδ/NFκB and IL-8 production were inhibited by rottlerin (a nonspecific PKCδ inhibitor) and by an overexpression of dominant-negative PKCδ. In vivo LPA administration in mice leads to increased levels of a murine homolog of IL-8 and of neutrophils in the bronchoalveolar fluid [88]. Moreover, LPA signaling induces EGFR transactivation via Lyn kinase, from Src kinase family, to promote matrix metalloprotease (MMP) secretion as well as IL-8 [89]. Additionally, activation of the signal transducers and activators of the transcription 3 (STAT3) in alveolar epithelial cells during host defense promotes inflammation and spontaneous lung cancer [90]. Through these signaling cascades, a chronic inflammation is pursued and could lead to malignant transformation. In lung cancer, inhibition of ATX-LPA axis reduced cell migration, invasion, and vascularization in a 3-D lung cancer xenograft model [91]. There is evidence that ATX is highly expressed in poorer differentiated lung carcinomas, particularly in tumor-adjacent B lymphocytes [92] and that LPA5 may play a key role in the progression of these carcinomas [68], while LPA3 could have a protective role [66]. Furthermore, LPA and other phospholipid levels are upregulated as a side effect of chemo- and radiotherapy, inducing a prometastatic microenvironment in lung cancer [93]. Interestingly, LPA did not induce proliferation nor survival in these cells, but rather an increase in motility, adhesion to bone marrow stroma, and enhanced secretion of ATP, another potent chemokinetic factor, from stroma cells [93]. Together, evidence suggests a significant role of ATX-LPA axis in inflammation and lung cancer through the increase of proinflammatory cytokines.

4.2. Breast

In breast cancer (BCa), the ATX-LPA axis induces inflammation and tumor formation in the mammary gland through LPA1–3 and high ATX expression, which is produced in the adjacent mammary adipose tissue rather than actual cancer cells [94, 95]. Individual overexpression of each of the EDG family receptors, but especially of LPA2, induced a high frequency of late-onset, estrogen receptor (ER) positive, and invasive and metastatic mammary cancer [94]. Moreover, bone metastases are frequent in BCa; ATX expression in these tumors can control the progression of osteolytic bone metastases in vivo through the procoagulant activity of BCa cells that induce platelet-derived LPA [96].

ATX-LPA axis is a strong inducer of inflammatory mediators like IL-8, IL-6, TNF-α, and growth factors such as the vascular endothelial growth factor (VEGF) and the granulocyte colony-stimulating factor (G-CSF) [95]. Some molecules (IL-8 and VEGF) were detected earlier than tumorigenesis in vivo [94]. Inhibition of ATX induced a twofold reduction in at least 20 of these inflammatory mediators in the tumor-adjacent mammary adipose tissue-reducing inflammation and tumorigenesis [95]. Additionally, expression of LPA1–3 increased phosphorylation of STAT3, STAT5, NFκB and ATF2, and master inflammatory transcription factors, in mouse mammary carcinomas [94]. Furthermore, cytokines produced in the microenvironment (i.e., IL-6) can activate STAT3 through its receptors inducing an inflammatory loop [97]. Adipose tissue adjacent to breast tumors stimulates autotaxin (ATX) secretion, which increases tumor growth and metastasis [19]. Interestingly, radiotherapy in adipose tissue of rats and humans increased mRNA expression of ATX, multiple inflammatory mediators, and LPA1–2. Such effect could promote LPA signaling and further inflammatory signaling, which in turn could potentially protect cancer cells from subsequent radiation therapy [98]. ATX inhibition reduced the leukocyte infiltration and tumor growth in vivo [95]. All these evidence suggest that chronic inflammation contributes to tumor development in BCa. Controlling inflammation and cancer progression could be achieved by targeting the ATX-LPA axis.

4.3. Ovary

In ovarian cancer (OC), ATX is highly expressed and secreted by cancer cells [99]. Therefore, LPA is present at high concentrations in the ascites fluid of OC patients compared to benign and healthy controls and has been proposed as a potential biomarker [100102]. LPA acts as a growth factor and prevents apoptosis in OC cells by signaling through redox-dependent activation of ERK, AKT, and NFκB signaling pathways. Inhibiting ROS production blocked LPA/NFκB signaling and cell proliferation [103]. Additionally, LPA has been shown to upregulate the expression of human telomerase reverse transcriptase (hTERT) and telomerase activity in OC cell lines, through a PI3K and HIF-1α-dependent mechanism, enabling replicative immortality [104]. On the other hand, OC cell lines, SKOV-3, and OVCAR3 that expressed increased LPA1–3 receptors showed more invasiveness compared to knockdowns. Moreover, via LPA2–3, OC cells promote production of IL-6, IL-8, and VEGF in vitro [105] and induced urokinase plasminogen activator (uPA) secretion in a MAPK- (p38) and PI3K-dependent mechanism that required Src kinase for optimal MAPK phosphorylation, enhancing OC invasion [106].

4.4. Liver

Liver cirrhosis, a terminal stage of chronic inflammatory and fibrotic liver diseases, and chronic hepatitis C are distinct risk factors for hepatocellular carcinoma (HCC) [107, 108]. Increased serum ATX activity and plasma LPA levels have been found in patients with chronic hepatitis C in association with a histological stage of liver fibrosis [108]. Furthermore, in HCC, ATX is expressed in 89% of tumor tissues, especially in those with cirrhosis or hepatitis C, compared to 20% in normal hepatocytes [109]. Additionally, in HCC cell lines, TNF-α/NFκB pathway, known to contribute to inflammation-associated cancer, was shown to upregulate ATX expression and LPA production. The latter resulted in an increased cellular invasion [109]. Similarly, LPA modulates tumor microenvironment by inducing transdifferentiation of peritumoral fibroblasts to a CAF-like myofibroblastic phenotype which enhances proliferation, migration, and invasion in HCC [110]. Additionally, LPA6 mediates tumor growth and tumorigenicity by upregulating Pim-3 protooncogene through a STAT3-dependent mechanism [69]. Recently, human cirrhosis regulatory gene modules were identified through a transcriptome meta-analysis [107]. This analysis provides an overview of a molecular dysregulation common to a wide range of liver disease etiologies in which the ATX-LPA axis is a central regulator [107]. This study marks a great breakthrough in the area and provides a promising target for HCC chemoprevention through this axis; mainly due to the compounds of ongoing clinical trials on idiopathic pulmonary fibrosis and systemic sclerosis (Table 1). If approved, they could be tested as preventive therapy in cirrhosis patients and as adjuvant therapy in HCC [107, 111].


NameTargetMechanism of actionPhaseIndication/modelReference

HA130ATXIt binds to the active site of ATX (T210).
IC50 = 28 nM in vitro
PreclinicalMelanoma[25]
PF-8380ATXDirect binding to ATX. Inhibits lysoPLD activity.
IC50 = 2.8 nM isolated ATX
IC50 = 101 nM in vivo
Preclinical(i) Inflammation
(ii) Glioblastoma
[133135]
ONO-8430506ATXDirect binding to ATX. Inhibits lysoPLD activity.
IC50 = 4.5 nM isolated ATX
IC50 = 4.1–11.6 nM in vivo
Preclinical(i) Breast cancer
(ii) BCa metastasis
(iii) Thyroid cancer
[19, 28, 121, 136]
GLPG1690ATXBinding to the hydrophobic pocket and hydrophobic channel of the protein.
IC50 = 131 nM in vitro
Phase IIIdiopathic pulmonary fibrosis[137, 138]
BMS-986020LPA1Inhibits signaling by LPA1Phase IIIdiopathic pulmonary fibrosis[139, 140]
SAR100842LPA1LPA1 antagonistPhase IISystemic sclerosis[141]
BrP-LPAATX
LPA1
LPA2
LPA3
LPA4
LPA5
Direct binding to ATX. Inhibits lysoPLD activity.
IC50: 600 nM ex vivo
Direct binding and inhibition of LPA1–5
Preclinical(i) Rheumatoid arthritis
(ii) Breast cancer
(iii) Pancreatic cancer
(iv) Glioma
[142145]

4.5. Colon

In human colorectal cancer (CC), expression of LPA1 and LPA2 is increased compared to normal mucosa. Conversely, LPA3 has a low expression in malignant tissues [112]. Evidence suggests a probable role of LPA1/2 receptors in CC. Furthermore, LPA-stimulated proliferation through the MAPK pathway, as well as migration through Rho kinase, and chemoresistance through the PI3K/AKT pathway [113]. Inflammation is an established risk for developing CC. Interestingly, in a colitis-associated mice cancer model, Lpar2−/− showed a decrease in tumor incidence and in progression to colon adenocarcinomas by reducing proliferation and proinflammatory factors such as monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) [114]. The latter affected the infiltration of macrophages to the tumor microenvironment [114]. Moreover, although LPA increased tumor incidence in ApcMin/+ mice predisposed to adenomas, in Lpar2−/− ApcMin/+, tumor incidence was reduced by 50% [114, 115]. In addition, the expression levels of KLF5, cyclin D1, c-Myc, and HIF-1α were lower compared to ApcMin/+ mice, while β-catenin was primarily cytoplasmic in Lpar2−/− ApcMin/+ mice compared to its nuclear localization in ApcMin/+ mice [115]. This evidence suggests an important role of ATX-LPA axis in tumorigenesis derived from colon chronic inflammation.

4.6. Others

Along with cancers previously described, ATX-LPA axis and its signaling pathways have been studied in several other carcinomas such as melanoma, where LPA signaling suppresses antigen receptor signaling, cell activation, and proliferation in CD8 T cells that express LPA5, inhibiting immune response [116] and promoting tumorigenesis. In pancreatic cancer, LPA1 and LPA3 promote proliferation, invasion through MMP2 secretion, and activation of focal adhesion kinase (FAK) and Paxillin, as well as drug resistance [117, 118]. In glioblastoma multiforme (GBM), an increased ATX-LPA axis has been described to promote cell proliferation and migration through LPA1 [119]. GBM is also characterized by high levels of inflammatory mediators and activation of AKT and NFκB signaling pathways, although the link between ATX-LPA and inflammation remains to be studied [120]. In thyroid cancer, ATX is highly expressed in papillary thyroid carcinomas compared with benign neoplasm [121]. ATX-LPA axis induces at least 16 inflammatory mediators, including IL1-β, IL6, IL8, G-CSF, and TNF-α in vivo; at the same time, these mediators induce ATX expression and increase LPA levels. Blocking the ATX-LPA axis induced a reduction of inflammatory mediators, tumor volume, and angiogenesis [121]. In renal cell carcinoma, ATX-LPA axis is associated to chemoresistance through LPA1. Coadministration of Ki16425, an LPA1/3 antagonist, with sunitinib, a tyrosine kinase inhibitor, prolonged the responsiveness of renal cell carcinoma to sunitinib in xenograft models [122].

So far, the evidence shows that ATX-LPA signaling in cancer is more complex than previously thought. In addition to promoting proliferation, aggressiveness, and metastasis, it induces an enabling inflammatory setting (Figure 3) and contributes to the differentiation of CAFs [123], leukocyte infiltration [92, 116], angiogenesis [123], and stem cell maintenance [99]; all of them are important components of tumor microenvironment (Figure 4). Thus, the ATX-LPA axis represents a crucial target to reduce CRI and cancer progression.

5. Targeting Autotaxin-LPA Axis for Cancer Therapy

LPA signaling is regulated by ATX activity, LPA receptors, and LPA degradation by LPP1 and LPAAT [125, 126]. In numerous cancers, ATX protein is overexpressed, leading to increased LPA levels in the tumor microenvironment and peripheral blood [99, 101, 127]. Cancer cells have a higher LPA receptor content on their cell surface compared to normal and benign cells and a downregulated expression of LPPs [128]. Therefore, targeting LPA signaling through these components is currently under study and constantly reviewed [4, 127, 129132]. In this section, we summarize some of the drugs studied regarding ATX inhibition and LPA receptor antagonism (Table 1).

ATX-LPA axis has been shown to induce chemoresistance by upregulating antioxidant genes, multidrug-resistant transporters (ABCC1, ABCG2, ABCC2, and ABCC3), aldehyde dehydrogenase 1 (ALDH1), and stem cell maintenance [99, 136]. Additionally, ATX is among the top 40 most upregulated genes in metastatic cancer [146]. Therefore, inhibition of the axis has shown great results as adjuvant therapy to enhance both chemo- and radiotherapy in vitro and in vivo, as well as tumor growth reduction. Additionally, as we described, CRI is an enabling setting for tumor development. We suggest that a strategy to be considered regarding the ATX-LPA axis in CRI should be a multitarget approach, where both proinflammatory cytokines and ATX-LPA are taken into consideration for better outcomes.

Currently, drugs of ongoing clinical trials are for noncancer diseases; nevertheless, once approved, they could be tested in various cancers. Meanwhile, improvement of physiological and pathological knowledge regarding signal transduction by this axis will lead to the development of more specific therapeutic drugs to better target this signaling cascade.

6. Conclusions

The ATX-LPA signaling pathway is physiologically relevant during development and adulthood. Dysregulation of this axis is linked to several pathologies, including inflammation-related conditions such as rheumatoid arthritis, fibrosis, neuropathic pain, and cancer. In cancer, it has a major involvement in key components of the microenvironment, including leukocyte infiltration, angiogenesis, and decreased immune response. Interestingly, this axis has been shown to mediate cancer-related inflammation through diverse signaling pathways, crosstalk, and positive loops. Therefore, it enhances a proinflammatory microenvironment and, at the same time, ATX-LPA signaling augments. Breaking the inflammatory cycle and blocking LPA signaling and production should provide an innovative treatment for cancer by decreasing CRI, tumor growth, metastasis, and resistance to cancer treatments. Recent evidence in cirrhosis patients point to this axis as a key regulator in HCC tumorigenesis, providing a very interesting potential target for cancer prevention.

As we wait for ATX-LPA inhibitors to move from preclinical into clinical trials, further investigation is needed regarding this complex signaling pathway to achieve more efficient therapeutics in cancer and other ATX-LPA axis-related pathologies.

Abbreviations

LPA:Lysophosphatidic acid
GPCR:G protein-coupled receptor
ATX:Autotaxin
PC:Phosphatidylcholine
PS:Phosphatidylserine
PE:Phosphatidylethanolamine
PLA1:Phospholipase A1
PLA2:Phospholipase A2
LPC:Lysophosphatidylcholine
PA:Phosphatidic acid
PLD:Phospholipase D
sPLA2:Secreted phospholipase A2
LPP1:Lipid phosphate phosphohydrolase type 1
MAG:Monoacylglycerol
LPAAT:Lysophosphatidic acid acyltransferase
LPE:Lysophosphatidylethanolamine
LPS:Lysophosphatidylserine
cPLA2:Cytosolic phospholipase A2
AC:Adenylyl cyclase
EDG family:Endothelial differentiation gene family
Vgz-1:Ventricular zone gene-1
CNS:Central nervous system
COX-2:Cyclooxygenase-2
HCC:Hepatocellular carcinoma
CRI:Cancer-related inflammation
PKC:Protein kinase C
HBEpCs:Human bronchial epithelial cells
MMP:Matrix metalloprotease
Stat:Signal transducers and activators of the transcription
BCa:Breast cancer
ER:Estrogen receptor
IL:Interleukin
TNF-α:Tumor necrosis factor α
VEGF:Vascular endothelial growth factor
G-CSF:Granulocyte colony-stimulating factor
NFκB:Nuclear factor kappa-light-chain-enhancer of activated B cells
ATF2:Activating transcription factor 2
OC:Ovarian cancer
ROS:Reactive oxygen species
hTERT:Human telomerase reverse transcriptase
HIF-1α:Hypoxia-inducible factor-1α
uPA:Urokinase plasminogen activator
MCP-1:Monocyte chemoattractant protein-1
MIF:Macrophage migration inhibitory factor
KLF5:Krüpple-like factor 5
FAK:Focal adhesion kinase
GBM:Glioblastoma multiforme
CAF:Cancer-associated fibroblast
EGFR:Epidermal growth factor receptor
ECM:Extracellular matrix
ALDH1:Aldehyde dehydrogenase 1.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Acknowledgments

This work was supported by UNAM-PAPIIT IA200718. Silvia Anahi Valdés-Rives is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), and received Fellowship 582548 from CONACYT.

References

  1. W. H. Moolenaar, “Development of our current understanding of bioactive lysophospholipids,” Annals of the New York Academy of Sciences, vol. 905, pp. 1–10, 2000. View at: Publisher Site | Google Scholar
  2. K. Bandoh, J. Aoki, A. Taira, M. Tsujimoto, H. Arai, and K. Inoue, “Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species,” FEBS Letters, vol. 478, no. 1-2, pp. 159–165, 2000. View at: Publisher Site | Google Scholar
  3. W. H. Moolenaar, L. A. van Meeteren, and B. N. G. Giepmans, “The ins and outs of lysophosphatidic acid signaling,” BioEssays, vol. 26, no. 8, pp. 870–881, 2004. View at: Publisher Site | Google Scholar
  4. I. Gonzalez-Gil, D. Zian, H. Vazquez-Villa, S. Ortega-Gutierrez, and M. L. Lopez-Rodriguez, “The status of the lysophosphatidic acid receptor type 1 (LPA1R),” MedChemComm, vol. 6, no. 1, pp. 13–23, 2015. View at: Publisher Site | Google Scholar
  5. G. B. Mills and W. H. Moolenaar, “The emerging role of lysophosphatidic acid in cancer,” Nature Reviews Cancer, vol. 3, no. 8, pp. 582–591, 2003. View at: Publisher Site | Google Scholar
  6. J. W. Choi and J. Chun, “Lysophospholipids and their receptors in the central nervous system,” Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1831, no. 1, pp. 20–32, 2013. View at: Publisher Site | Google Scholar
  7. Y. C. Yung, N. C. Stoddard, and J. Chun, “LPA receptor signaling: pharmacology, physiology, and pathophysiology,” Journal of Lipid Research, vol. 55, no. 7, pp. 1192–1214, 2014. View at: Publisher Site | Google Scholar
  8. J. Mazereeuw-Hautier, S. Gres, M. Fanguin et al., “Production of lysophosphatidic acid in blister fluid: involvement of a lysophospholipase D activity,” Journal of Investigative Dermatology, vol. 125, no. 3, pp. 421–427, 2005. View at: Publisher Site | Google Scholar
  9. L. A. van Meeteren and W. H. Moolenaar, “Regulation and biological activities of the autotaxin–LPA axis,” Progress in Lipid Research, vol. 46, no. 2, pp. 145–160, 2007. View at: Publisher Site | Google Scholar
  10. C. Pagès, M.-F. Simon, P. Valet, and J. S. Saulnier-Blache, “Lysophosphatidic acid synthesis and release,” Prostaglandins & Other Lipid Mediators, vol. 64, no. 1–4, pp. 1–10, 2001. View at: Publisher Site | Google Scholar
  11. T. Sano, D. Baker, T. Virag et al., “Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood,” Journal of Biological Chemistry, vol. 277, no. 24, pp. 21197–21206, 2002. View at: Publisher Site | Google Scholar
  12. D. L. Baker, D. M. Desiderio, D. D. Miller, B. Tolley, and G. J. Tigyi, “Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography–mass spectrometry,” Analytical Biochemistry, vol. 292, no. 2, pp. 287–295, 2001. View at: Publisher Site | Google Scholar
  13. J. W. Choi, D. R. Herr, K. Noguchi et al., “LPA receptors: subtypes and biological actions,” Annual Review of Pharmacology and Toxicology, vol. 50, no. 1, pp. 157–186, 2010. View at: Publisher Site | Google Scholar
  14. J. Aoki, A. Inoue, and S. Okudaira, “Two pathways for lysophosphatidic acid production,” Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1781, no. 9, pp. 513–518, 2008. View at: Publisher Site | Google Scholar
  15. A. Perrakis and W. H. Moolenaar, “Autotaxin: structure-function and signaling,” Journal of Lipid Research, vol. 55, no. 6, pp. 1010–1018, 2014. View at: Publisher Site | Google Scholar
  16. H. Kawagoe, O. Soma, J. Goji et al., “Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2),” Genomics, vol. 30, no. 2, pp. 380–384, 1995. View at: Publisher Site | Google Scholar
  17. A. Tokumura, E. Majima, Y. Kariya et al., “Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase,” Journal of Biological Chemistry, vol. 277, no. 42, pp. 39436–39442, 2002. View at: Publisher Site | Google Scholar
  18. M. Umezu-Goto, Y. Kishi, A. Taira et al., “Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production,” The Journal of Cell Biology, vol. 158, no. 2, pp. 227–233, 2002. View at: Publisher Site | Google Scholar
  19. M. G. K. Benesch, X. Tang, T. Maeda et al., “Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice,” The FASEB Journal, vol. 28, no. 6, pp. 2655–2666, 2014. View at: Publisher Site | Google Scholar
  20. L. A. Van Meeteren, P. Ruurs, C. Stortelers et al., “Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development,” Molecular and Cellular Biology, vol. 26, no. 13, pp. 5015–5022, 2006. View at: Publisher Site | Google Scholar
  21. M. Tanaka, S. Okudaira, Y. Kishi et al., “Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid,” Journal of Biological Chemistry, vol. 281, no. 35, pp. 25822–25830, 2006. View at: Publisher Site | Google Scholar
  22. R. Dusaulcy, C. Rancoule, S. Grès et al., “Adipose-specific disruption of autotaxin enhances nutritional fattening and reduces plasma lysophosphatidic acid,” Journal of Lipid Research, vol. 52, no. 6, pp. 1247–1255, 2011. View at: Publisher Site | Google Scholar
  23. M. G. K. Benesch, Y. M. Ko, T. P. W. McMullen, and D. N. Brindley, “Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions,” FEBS Letters, vol. 588, no. 16, pp. 2712–2727, 2014. View at: Publisher Site | Google Scholar
  24. G. Ferry, E. Tellier, A. Try et al., “Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity,” Journal of Biological Chemistry, vol. 278, no. 20, pp. 18162–18169, 2003. View at: Publisher Site | Google Scholar
  25. H. M. H. G. Albers, A. Dong, L. A. van Meeteren et al., “Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 16, pp. 7257–7262, 2010. View at: Publisher Site | Google Scholar
  26. J. L. Tomsig, A. H. Snyder, E. V. Berdyshev et al., “Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo,” Biochemical Journal, vol. 419, no. 3, pp. 611–618, 2009. View at: Publisher Site | Google Scholar
  27. X. Tang, M. G. K. Benesch, and D. N. Brindley, “Lipid phosphate phosphatases and their roles in mammalian physiology and pathology,” Journal of Lipid Research, vol. 56, no. 11, pp. 2048–2060, 2015. View at: Publisher Site | Google Scholar
  28. M. G. K. Benesch, Y. Y. Zhao, J. M. Curtis, T. P. W. McMullen, and D. N. Brindley, “Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate,” Journal of Lipid Research, vol. 56, no. 6, pp. 1134–1144, 2015. View at: Publisher Site | Google Scholar
  29. V. A. Blaho and T. Hla, “Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors,” Chemical Reviews, vol. 111, no. 10, pp. 6299–6320, 2011. View at: Publisher Site | Google Scholar
  30. Y. Kihara, M. Maceyka, S. Spiegel, and J. Chun, “Lysophospholipid receptor nomenclature review: IUPHAR review 8,” British Journal of Pharmacology, vol. 171, no. 15, pp. 3575–3594, 2014. View at: Publisher Site | Google Scholar
  31. J. Chun, T. Hla, K. R. Lynch, S. Spiegel, and W. H. Moolenaar, “International union of basic and clinical pharmacology. LXXVIII. Lysophospholipid receptor nomenclature,” Pharmacological Reviews, vol. 62, no. 4, pp. 579–587, 2010. View at: Publisher Site | Google Scholar
  32. Y. Takuwa, N. Takuwa, and N. Sugimoto, “The Edg family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities,” The Journal of Biochemistry, vol. 131, no. 6, pp. 767–771, 2002. View at: Publisher Site | Google Scholar
  33. K. Yanagida, Y. Kurikawa, T. Shimizu, and S. Ishii, “Current progress in non-Edg family LPA receptor research,” Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1831, no. 1, pp. 33–41, 2013. View at: Publisher Site | Google Scholar
  34. J. R. Williams, A. L. Khandoga, P. Goyal et al., “Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation,” Journal of Biological Chemistry, vol. 284, no. 25, pp. 17304–17319, 2009. View at: Publisher Site | Google Scholar
  35. J. H. Hecht, J. A. Weiner, S. R. Post, and J. Chun, “Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex,” The Journal of Cell Biology, vol. 135, no. 4, pp. 1071–1083, 1996. View at: Publisher Site | Google Scholar
  36. S. An, T. Bleu, O. G. Hallmark, and E. J. Goetzl, “Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid,” Journal of Biological Chemistry, vol. 273, no. 14, pp. 7906–7910, 1998. View at: Publisher Site | Google Scholar
  37. K. Bandoh, J. Aoki, H. Hosono et al., “Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid,” Journal of Biological Chemistry, vol. 274, no. 39, pp. 27776–27785, 1999. View at: Publisher Site | Google Scholar
  38. D. S. Im, C. E. Heise, M. A. Harding et al., “Molecular cloning and characterization of a lysophosphatidic acid receptor, Edg-7, expressed in prostate,” Molecular Pharmacology, vol. 57, no. 4, pp. 753–759, 2000. View at: Publisher Site | Google Scholar
  39. J. J. Contos, I. Ishii, and J. Chun, “Lysophosphatidic acid receptors,” Molecular Pharmacology, vol. 58, no. 6, pp. 1188–1196, 2000. View at: Publisher Site | Google Scholar
  40. Y. C. Yung, N. C. Stoddard, H. Mirendil, and J. Chun, “Lysophosphatidic acid signaling in the nervous system,” Neuron, vol. 85, no. 4, pp. 669–682, 2015. View at: Publisher Site | Google Scholar
  41. J. J. A. Contos, N. Fukushima, J. A. Weiner, D. Kaushal, and J. Chun, “Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior,” Proceedings of the National Academy of Sciences, vol. 97, no. 24, pp. 13384–13389, 2000. View at: Publisher Site | Google Scholar
  42. H. Ueda, H. Matsunaga, O. I. Olaposi, and J. Nagai, “Lysophosphatidic acid: chemical signature of neuropathic pain,” Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1831, no. 1, pp. 61–73, 2013. View at: Publisher Site | Google Scholar
  43. Y.-J. Lai, C.-S. Chen, W.-C. Lin, and F.-T. Lin, “C-Src-mediated phosphorylation of TRIP6 regulates its function in lysophosphatidic acid-induced cell migration,” Molecular and Cellular Biology, vol. 25, no. 14, pp. 5859–5868, 2005. View at: Publisher Site | Google Scholar
  44. Y.-J. Lai, W.-C. Lin, and F.-T. Lin, “PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration,” Journal of Biological Chemistry, vol. 282, no. 33, pp. 24381–24387, 2007. View at: Publisher Site | Google Scholar
  45. H. Ohuchi, A. Hamada, H. Matsuda et al., “Expression patterns of the lysophospholipid receptor genes during mouse early development,” Developmental Dynamics, vol. 237, no. 11, pp. 3280–3294, 2008. View at: Publisher Site | Google Scholar
  46. J. J. A. Contos, I. Ishii, N. Fukushima et al., “Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa2,” Molecular and Cellular Biology, vol. 22, no. 19, pp. 6921–6929, 2002. View at: Publisher Site | Google Scholar
  47. I. Ishii, J. J. Contos, N. Fukushima, and J. Chun, “Functional comparisons of the lysophosphatidic acid receptors, LPA1/VZG-1/EDG-2, LPA2/EDG-4, and LPA3/EDG-7 in neuronal cell lines using a retrovirus expression system,” Molecular Pharmacology, vol. 58, no. 5, pp. 895–902, 2000. View at: Publisher Site | Google Scholar
  48. X. Ye, K. Hama, J. J. A. Contos et al., “LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing,” Nature, vol. 435, no. 7038, pp. 104–108, 2005. View at: Publisher Site | Google Scholar
  49. X. Ye, M. K. Skinner, G. Kennedy, and J. Chun, “Age-dependent loss of sperm production in mice via impaired lysophosphatidic acid signaling,” Biology of Reproduction, vol. 79, no. 2, pp. 328–336, 2008. View at: Publisher Site | Google Scholar
  50. K. Noguchi, S. Ishii, and T. Shimizu, “Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family,” Journal of Biological Chemistry, vol. 278, no. 28, pp. 25600–25606, 2003. View at: Publisher Site | Google Scholar
  51. K. Kotarsky, Å. Boketoft, J. Bristulf et al., “Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes,” Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 2, pp. 619–628, 2006. View at: Publisher Site | Google Scholar
  52. C.-W. Lee, R. Rivera, S. Gardell, A. E. Dubin, and J. Chun, “GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5,” Journal of Biological Chemistry, vol. 281, no. 33, pp. 23589–23597, 2006. View at: Publisher Site | Google Scholar
  53. K. Yanagida, K. Masago, H. Nakanishi et al., “Identification and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6,” Journal of Biological Chemistry, vol. 284, no. 26, pp. 17731–17741, 2009. View at: Publisher Site | Google Scholar
  54. M. Lee, S. Choi, G. Halldén, S. J. Yo, D. Schichnes, and G. W. Aponte, “P2Y5 is a Gαi, Gα12/13 G protein-coupled receptor activated by lysophosphatidic acid that reduces intestinal cell adhesion,” American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 297, no. 4, pp. G641–G654, 2009. View at: Publisher Site | Google Scholar
  55. S. M. Pasternack, I. von Kügelgen, K. Al Aboud et al., “G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth,” Nature Genetics, vol. 40, no. 3, pp. 329–334, 2008. View at: Publisher Site | Google Scholar
  56. R. Janssens, J. M. Boeynaems, M. Godart, and D. Communi, “Cloning of a human heptahelical receptor closely related to the P2Y5receptor,” Biochemical and Biophysical Research Communications, vol. 236, no. 1, pp. 106–112, 1997. View at: Publisher Site | Google Scholar
  57. C.-W. Lee, R. Rivera, A. E. Dubin, and J. Chun, “LPA4/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing Gs-, Gq/Gi-mediated calcium signaling and G12/13-mediated rho activation,” Journal of Biological Chemistry, vol. 282, no. 7, pp. 4310–4317, 2007. View at: Publisher Site | Google Scholar
  58. Z. Lee, C.-T. Cheng, H. Zhang et al., “Role of LPA4/p2y9/GPR23 in negative regulation of cell motility,” Molecular Biology of the Cell, vol. 19, no. 12, pp. 5435–5445, 2008. View at: Publisher Site | Google Scholar
  59. H. Sumida, K. Noguchi, Y. Kihara et al., “LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis,” Blood, vol. 116, no. 23, pp. 5060–5070, 2010. View at: Publisher Site | Google Scholar
  60. S. Amisten, O. O. Braun, A. Bengtsson, and D. Erlinge, “Gene expression profiling for the identification of G-protein coupled receptors in human platelets,” Thrombosis Research, vol. 122, no. 1, pp. 47–57, 2008. View at: Publisher Site | Google Scholar
  61. Z. Callaerts-Vegh, S. Leo, B. Vermaercke, T. Meert, and R. D’Hooge, “LPA5 receptor plays a role in pain sensitivity, emotional exploration and reversal learning,” Genes, Brain and Behavior, vol. 11, pp. 1009–1019, 2012. View at: Publisher Site | Google Scholar
  62. M.-E. Lin, R. R. Rivera, and J. Chun, “Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain,” The Journal of Biological Chemistry, vol. 287, no. 21, pp. 17608–17617, 2012. View at: Publisher Site | Google Scholar
  63. K. Takahashi, K. Fukushima, Y. Onishi et al., “Lysophosphatidic acid (LPA) signaling via LPA4 and LPA6 negatively regulates cell motile activities of colon cancer cells,” Biochemical and Biophysical Research Communications, vol. 483, no. 1, pp. 652–657, 2017. View at: Publisher Site | Google Scholar
  64. M. Araki, M. Kitayoshi, Y. Dong et al., “Inhibitory effects of lysophosphatidic acid receptor-5 on cellular functions of sarcoma cells,” Growth Factors, vol. 32, no. 3-4, pp. 117–122, 2014. View at: Publisher Site | Google Scholar
  65. M. Jongsma, E. Matas-Rico, A. Rzadkowski, K. Jalink, and W. H. Moolenaar, “LPA is a chemorepellent for B16 melanoma cells: action through the cAMP-elevating LPA5 receptor,” PLoS One, vol. 6, no. 12, article e29260, 2011. View at: Publisher Site | Google Scholar
  66. M. Hayashi, K. Okabe, Y. Yamawaki et al., “Loss of lysophosphatidic acid receptor-3 enhances cell migration in rat lung tumor cells,” Biochemical and Biophysical Research Communications, vol. 405, no. 3, pp. 450–454, 2011. View at: Publisher Site | Google Scholar
  67. K. Harper, D. Arsenault, S. Boulay-Jean, A. Lauzier, F. Lucien, and C. M. Dubois, “Autotaxin promotes cancer invasion via the lysophosphatidic acid receptor 4: participation of the cyclic AMP/EPAC/Rac1 signaling pathway in invadopodia formation,” Cancer Research, vol. 70, no. 11, pp. 4634–4643, 2010. View at: Publisher Site | Google Scholar
  68. K. Okabe, M. Hayashi, Y. Yamawaki et al., “Possible involvement of lysophosphatidic acid receptor-5 gene in the acquisition of growth advantage of rat tumor cells,” Molecular Carcinogenesis, vol. 50, no. 8, pp. 635–642, 2011. View at: Publisher Site | Google Scholar
  69. A. Mazzocca, F. Dituri, F. De Santis et al., “Lysophosphatidic acid receptor LPAR6 supports the tumorigenicity of hepatocellular carcinoma,” Cancer Research, vol. 75, no. 3, pp. 532–543, 2015. View at: Publisher Site | Google Scholar
  70. F. Balkwill and A. Mantovani, “Inflammation and cancer: back to Virchow?” The Lancet, vol. 357, no. 9255, pp. 539–545, 2001. View at: Publisher Site | Google Scholar
  71. F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani, “Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability,” Carcinogenesis, vol. 30, no. 7, pp. 1073–1081, 2009. View at: Publisher Site | Google Scholar
  72. S. Deivendran, K. H. Marzook, and M. Radhakrishna Pillai, “The role of inflammation in cervical cancer,” Advances in Experimental Medicine and Biology, vol. 816, pp. 377–399, 2014. View at: Publisher Site | Google Scholar
  73. J. G. Fox and T. C. Wang, “Inflammation, atrophy, and gastric cancer,” The Journal of Clinical Investigation, vol. 117, no. 1, pp. 60–69, 2007. View at: Publisher Site | Google Scholar
  74. H. Barash, E. R. Gross, Y. Edrei et al., “Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 5, pp. 2207–2212, 2010. View at: Publisher Site | Google Scholar
  75. D. G. DeNardo and L. M. Coussens, “Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression,” Breast Cancer Research, vol. 9, no. 4, p. 212, 2007. View at: Publisher Site | Google Scholar
  76. A. M. Al Murri, J. M. S. Bartlett, P. A. Canney, J. C. Doughty, C. Wilson, and D. C. McMillan, “Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer,” British Journal of Cancer, vol. 94, no. 2, pp. 227–230, 2006. View at: Publisher Site | Google Scholar
  77. N. Azad, Y. Rojanasakul, and V. Vallyathan, “Inflammation and lung cancer: roles of reactive oxygen/nitrogen species,” Journal of Toxicology and Environmental Health Part B: Critical Reviews, vol. 11, no. 1, pp. 1–15, 2008. View at: Publisher Site | Google Scholar
  78. K. S. Sfanos and A. M. De Marzo, “Prostate cancer and inflammation: the evidence,” Histopathology, vol. 60, no. 1, pp. 199–215, 2012. View at: Publisher Site | Google Scholar
  79. A. Macciò and C. Madeddu, “Inflammation and ovarian cancer,” Cytokine, vol. 58, no. 2, pp. 133–147, 2012. View at: Publisher Site | Google Scholar
  80. V. Guarino, M. D. Castellone, E. Avilla, and R. M. Melillo, “Thyroid cancer and inflammation,” Molecular and Cellular Endocrinology, vol. 321, no. 1, pp. 94–102, 2010. View at: Publisher Site | Google Scholar
  81. J. Liang, M. Nagahashi, E. Y. Kim et al., “Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer,” Cancer Cell, vol. 23, no. 1, pp. 107–120, 2013. View at: Publisher Site | Google Scholar
  82. E. R. Rayburn, S. J. Ezell, and R. Zhang, “Anti-inflammatory agents for cancer therapy,” Molecular and Cellular Pharmacology, vol. 1, no. 1, pp. 29–43, 2009. View at: Publisher Site | Google Scholar
  83. C. M. Ulrich, J. Bigler, and J. D. Potter, “Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics,” Nature Reviews Cancer, vol. 6, no. 2, pp. 130–140, 2006. View at: Publisher Site | Google Scholar
  84. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011. View at: Publisher Site | Google Scholar
  85. Z. Bai, L. Cai, E. Umemoto et al., “Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the Autotaxin/lysophosphatidic acid Axis,” The Journal of Immunology, vol. 190, no. 5, pp. 2036–2048, 2013. View at: Publisher Site | Google Scholar
  86. S. Knowlden and S. N. Georas, “The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and inflammation,” The Journal of Immunology, vol. 192, no. 3, pp. 851–857, 2014. View at: Publisher Site | Google Scholar
  87. D. N. Brindley, M. G. K. Benesch, and M. M. Murph, “Autotaxin–an enzymatic augmenter of malignant progression linked to inflammation,” in Melanoma - Current Clinical Management and Future Therapeutics, M. Murph, Ed., p. 12, InTech, Rijeka, 2015. View at: Google Scholar
  88. R. Cummings, Y. Zhao, D. Jacoby et al., “Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB activation and interleukin-8 secretion in human bronchial epithelial cells,” The Journal of Biological Chemistry, vol. 279, no. 39, pp. 41085–41094, 2004. View at: Publisher Site | Google Scholar
  89. Y. Zhao, D. He, B. Saatian et al., “Regulation of lysophosphatidic acid-induced epidermal growth factor receptor transactivation and interleukin-8 secretion in human bronchial epithelial cells by protein kinase Cδ, Lyn kinase, and matrix metalloproteinases,” The Journal of Biological Chemistry, vol. 281, no. 28, pp. 19501–19511, 2006. View at: Publisher Site | Google Scholar
  90. Y. Li, H. Du, Y. Qin, J. Roberts, O. W. Cummings, and C. Yan, “Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung,” Cancer Research, vol. 67, no. 18, pp. 8494–8503, 2007. View at: Publisher Site | Google Scholar
  91. X. Xu and G. D. Prestwich, “Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three-dimensional lung cancer xenograft model,” Cancer, vol. 116, no. 7, pp. 1739–1750, 2010. View at: Publisher Site | Google Scholar
  92. Y. Yang, L. Mou, N. Liu, and M. S. Tsao, “Autotaxin expression in non-small-cell lung cancer,” American Journal of Respiratory Cell and Molecular Biology, vol. 21, no. 2, pp. 216–222, 1999. View at: Publisher Site | Google Scholar
  93. G. Schneider, Z. P. Sellers, K. Bujko, S. S. Kakar, M. Kucia, and M. Z. Ratajczak, “Novel pleiotropic effects of bioactive phospholipids in human lung cancer metastasis,” Oncotarget, vol. 8, no. 35, pp. 58247–58263, 2017. View at: Publisher Site | Google Scholar
  94. S. Liu, M. Umezu-Goto, M. Murph et al., “Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases,” Cancer Cell, vol. 15, no. 6, pp. 539–550, 2009. View at: Publisher Site | Google Scholar
  95. M. G. K. Benesch, X. Tang, J. Dewald et al., “Tumor-induced inflammation in mammary adipose tissue stimulates a vicious cycle of autotaxin expression and breast cancer progression,” The FASEB Journal, vol. 29, no. 9, pp. 3990–4000, 2015. View at: Publisher Site | Google Scholar
  96. M. David, E. Wannecq, F. Descotes et al., “Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts,” PLoS One, vol. 5, no. 3, article e9741, 2010. View at: Publisher Site | Google Scholar
  97. H. Yu, D. Pardoll, and R. Jove, “STATs in cancer inflammation and immunity: a leading role for STAT3,” Nature Reviews Cancer, vol. 9, no. 11, pp. 798–809, 2009. View at: Publisher Site | Google Scholar
  98. G. Meng, X. Tang, Z. Yang et al., “Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy,” The FASEB Journal, vol. 31, no. 9, pp. 4064–4077, 2017. View at: Publisher Site | Google Scholar
  99. E. J. Seo, Y. W. Kwon, I. H. Jang et al., “Autotaxin regulates maintenance of ovarian cancer stem cells through lysophosphatidic acid-mediated autocrine mechanism,” Stem Cells, vol. 34, no. 3, pp. 551–564, 2016. View at: Publisher Site | Google Scholar
  100. Y. Xu, Z. Shen, D. W. Wiper et al., “Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers,” JAMA, vol. 280, no. 8, pp. 719–723, 1998. View at: Publisher Site | Google Scholar
  101. Y.-Y. Li, W.-C. Zhang, J.-L. Zhang et al., “Plasma levels of lysophosphatidic acid in ovarian cancer versus controls: a meta-analysis,” Lipids in Health and Disease, vol. 14, no. 1, p. 72, 2015. View at: Publisher Site | Google Scholar
  102. S.-Y. Zhang, W. Shi, P. Cheng, and M. J. Zaworotko, “A mixed-crystal lanthanide zeolite-like metal–organic framework as a fluorescent indicator for lysophosphatidic acid, a cancer biomarker,” Journal of the American Chemical Society, vol. 137, no. 38, pp. 12203–12206, 2015. View at: Publisher Site | Google Scholar
  103. J. A. Saunders, L. C. Rogers, C. Klomsiri, L. B. Poole, and L. W. Daniel, “Reactive oxygen species mediate lysophosphatidic acid induced signaling in ovarian cancer cells,” Free Radical Biology & Medicine, vol. 49, no. 12, pp. 2058–2067, 2010. View at: Publisher Site | Google Scholar
  104. K. Yang, D. Zheng, X. Deng, L. Bai, Y. Xu, and Y.-S. Cong, “Lysophosphatidic acid activates telomerase in ovarian cancer cells through hypoxia-inducible factor-1α and the PI3K pathway,” Journal of Cellular Biochemistry, vol. 105, no. 5, pp. 1194–1201, 2008. View at: Publisher Site | Google Scholar
  105. S. Yu, M. M. Murph, Y. Lu et al., “Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells,” Journal of the National Cancer Institute, vol. 100, no. 22, pp. 1630–1642, 2008. View at: Publisher Site | Google Scholar
  106. V. C. Estrella, A. M. Eder, S. Liu et al., “Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway,” International Journal of Oncology, vol. 31, no. 2, pp. 441–449, 2007. View at: Google Scholar
  107. S. Nakagawa, L. Wei, W. M. Song et al., “Molecular liver cancer prevention in cirrhosis by organ transcriptome analysis and lysophosphatidic acid pathway inhibition,” Cancer Cell, vol. 30, pp. 879–890, 2017. View at: Publisher Site | Google Scholar
  108. N. Watanabe, H. Ikeda, K. Nakamura et al., “Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C,” Journal of Clinical Gastroenterology, vol. 41, no. 6, pp. 616–623, 2007. View at: Publisher Site | Google Scholar
  109. J.-M. Wu, Y. Xu, N. J. Skill et al., “Autotaxin expression and its connection with the TNF-alpha-NF-κB axis in human hepatocellular carcinoma,” Molecular Cancer, vol. 9, no. 1, p. 71, 2010. View at: Publisher Site | Google Scholar
  110. A. Mazzocca, F. Dituri, L. Lupo, M. Quaranta, S. Antonaci, and G. Giannelli, “Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts,” Hepatology, vol. 54, no. 3, pp. 920–930, 2011. View at: Publisher Site | Google Scholar
  111. D. J. Erstad, A. M. Tager, Y. Hoshida, and B. C. Fuchs, “The autotaxin-lysophosphatidic acid pathway emerges as a therapeutic target to prevent liver cancer,” Molecular & Cellular Oncology, vol. 4, no. 3, article e1311827, 2017. View at: Publisher Site | Google Scholar
  112. D. Shida, T. Watanabe, J. Aoki et al., “Aberrant expression of lysophosphatidic acid (LPA) receptors in human colorectal cancer,” Laboratory Investigation, vol. 84, no. 10, pp. 1352–1362, 2004. View at: Publisher Site | Google Scholar
  113. H. Sun, J. Ren, Q. Zhu, F.-Z. Kong, L. Wu, and B.-R. Pan, “Effects of lysophosphatidic acid on human colon cancer cells and its mechanisms of action,” World Journal of Gastroenterology, vol. 15, no. 36, pp. 4547–4555, 2009. View at: Publisher Site | Google Scholar
  114. S. Lin, D. Wang, S. Iyer et al., “The absence of LPA2 attenuates tumor formation in an experimental model of colitis-associated cancer,” Gastroenterology, vol. 136, no. 5, pp. 1711–1720, 2009. View at: Publisher Site | Google Scholar
  115. S. Lin, S.-J. Lee, H. Shim, J. Chun, and C. C. Yun, “The absence of LPA receptor 2 reduces the tumorigenesis by APCMin mutation in the intestine,” American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 299, no. 5, pp. G1128–G1138, 2010. View at: Publisher Site | Google Scholar
  116. S. K. Oda, P. Strauch, Y. Fujiwara et al., “Lysophosphatidic acid inhibits CD8 T-cell activation and control of tumor progression,” Cancer Immunology Research, vol. 1, no. 4, pp. 245–255, 2013. View at: Publisher Site | Google Scholar
  117. Y. Liao, G. Mu, L. Zhang, W. Zhou, J. Zhang, and H. Yu, “Lysophosphatidic acid stimulates activation of focal adhesion kinase and paxillin and promotes cell motility, via LPA1–3, in human pancreatic cancer,” Digestive Diseases and Sciences, vol. 58, no. 12, pp. 3524–3533, 2013. View at: Publisher Site | Google Scholar
  118. K. Fukushima, K. Takahashi, E. Yamasaki et al., “Lysophosphatidic acid signaling via LPA1 and LPA3 regulates cellular functions during tumor progression in pancreatic cancer cells,” Experimental Cell Research, vol. 352, no. 1, pp. 139–145, 2017. View at: Publisher Site | Google Scholar
  119. Y. Kishi, S. Okudaira, M. Tanaka et al., “Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid,” The Journal of Biological Chemistry, vol. 281, no. 25, pp. 17492–17500, 2006. View at: Publisher Site | Google Scholar
  120. H. Wang, H. Wang, W. Zhang, H. J. Huang, W. S. L. Liao, and G. N. Fuller, “Analysis of the activation status of Akt, NFκB, and Stat3 in human diffuse gliomas,” Laboratory Investigation, vol. 84, no. 8, pp. 941–951, 2004. View at: Publisher Site | Google Scholar
  121. M. G. K. Benesch, Y. M. Ko, X. Tang et al., “Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer,” Endocrine-Related Cancer, vol. 22, no. 4, pp. 593–607, 2015. View at: Publisher Site | Google Scholar
  122. S.-C. Su, X. Hu, P. A. Kenney et al., “Autotaxin–lysophosphatidic acid signaling axis mediates tumorigenesis and development of acquired resistance to sunitinib in renal cell carcinoma,” Clinical Cancer Research, vol. 19, no. 23, pp. 6461–6472, 2013. View at: Publisher Site | Google Scholar
  123. E. S. Jeon, S. C. Heo, I. H. Lee et al., “Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1α from human mesenchymal stem cells,” Experimental & Molecular Medicine, vol. 42, no. 4, pp. 280–293, 2010. View at: Publisher Site | Google Scholar
  124. S. Liu, M. Murph, N. Panupinthu, and G. B. Mills, “ATX-LPA receptor axis in inflammation and cancer,” Cell Cycle, vol. 8, no. 22, pp. 3695–3701, 2009. View at: Publisher Site | Google Scholar
  125. D. N. Brindley, F.-T. Lin, and G. J. Tigyi, “Role of the autotaxin–lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy,” Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, vol. 1831, no. 1, pp. 74–85, 2013. View at: Publisher Site | Google Scholar
  126. B. P. C. Kok, G. Venkatraman, D. Capatos, and D. N. Brindley, “Unlike two peas in a pod: lipid phosphate phosphatases and phosphatidate phosphatases,” Chemical Reviews, vol. 112, no. 10, pp. 5121–5146, 2012. View at: Publisher Site | Google Scholar
  127. M. G. K. Benesch, X. Tang, G. Venkatraman, R. T. Bekele, and D. N. Brindley, “Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo,” The Journal of Biomedical Research, vol. 30, no. 4, pp. 272–284, 2016. View at: Publisher Site | Google Scholar
  128. N. Samadi, R. Bekele, D. Capatos, G. Venkatraman, M. Sariahmetoglu, and D. N. Brindley, “Regulation of lysophosphatidate signaling by autotaxin and lipid phosphate phosphatases with respect to tumor progression, angiogenesis, metastasis and chemo-resistance,” Biochimie, vol. 93, no. 1, pp. 61–70, 2011. View at: Publisher Site | Google Scholar
  129. Y. Kihara, H. Mizuno, and J. Chun, “Lysophospholipid receptors in drug discovery,” Experimental Cell Research, vol. 333, no. 2, pp. 171–177, 2015. View at: Publisher Site | Google Scholar
  130. D. Castagna, D. C. Budd, S. J. F. MacDonald, C. Jamieson, and A. J. B. Watson, “Development of autotaxin inhibitors: an overview of the patent and primary literature,” Journal of Medicinal Chemistry, vol. 59, no. 12, pp. 5604–5621, 2016. View at: Publisher Site | Google Scholar
  131. S. Llona-Minguez, A. Ghassemian, and T. Helleday, “Lysophosphatidic acid receptor (LPAR) modulators: the current pharmacological toolbox,” Progress in Lipid Research, vol. 58, pp. 51–75, 2015. View at: Publisher Site | Google Scholar
  132. J. L. Tanyi, Y. Hasegawa, R. Lapushin et al., “Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer,” Clinical Cancer Research, vol. 9, no. 10, Part 1, pp. 3534–3545, 2003. View at: Google Scholar
  133. J. Gierse, A. Thorarensen, K. Beltey et al., “A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation,” The Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 1, pp. 310–317, 2010. View at: Publisher Site | Google Scholar
  134. S. R. Bhave, D. Y. A. Dadey, R. M. Karvas et al., “Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines,” Frontiers in Oncology, vol. 3, p. 236, 2013. View at: Publisher Site | Google Scholar
  135. P.-D. St-Coeur, D. Ferguson, P. J. Morin, and M. Touaibia, “PF-8380 and closely related analogs: synthesis and structure-activity relationship towards autotaxin inhibition and glioma cell viability,” Archiv der Pharmazie, vol. 346, no. 2, pp. 91–97, 2013. View at: Publisher Site | Google Scholar
  136. G. Venkatraman, M. G. K. Benesch, X. Tang, J. Dewald, T. P. W. McMullen, and D. N. Brindley, “Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses: implications for cancer treatment,” The FASEB Journal, vol. 29, no. 3, pp. 772–785, 2015. View at: Publisher Site | Google Scholar
  137. N. Desroy, C. Housseman, X. Bock et al., “Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a first-in-class Autotaxin inhibitor undergoing clinical evaluation,” Journal of Medicinal Chemistry, vol. 60, no. 9, pp. 3580–3590, 2017. View at: Publisher Site | Google Scholar
  138. Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690, 2017, https://clinicaltrials.gov/ct2/show/NCT02738801?term=GLPG1690&rank=2.
  139. Safety and Efficacy of a Lysophosphatidic Acid Receptor Antagonist in Idiopathic Pulmonary Fibrosis, https://clinicaltrials.gov/ct2/show/record/NCT01766817.
  140. BMS-986020, http://bciq.biocentury.com/products/am152.
  141. Proof of Biological Activity of SAR100842 in Systemic Sclerosis, 2016, https://clinicaltrials.gov/ct2/show/record/NCT01651143?term=SAR100842&rank=1.
  142. I. Nikitopoulou, E. Kaffe, I. Sevastou et al., “A metabolically-stabilized phosphonate analog of lysophosphatidic acid attenuates collagen-induced arthritis,” PLoS One, vol. 8, no. 7, article e70941, 2013. View at: Publisher Site | Google Scholar
  143. H. Zhang, X. Xu, J. Gajewiak et al., “Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo,” Cancer Research, vol. 69, no. 13, pp. 5441–5449, 2009. View at: Publisher Site | Google Scholar
  144. M. Komachi, K. Sato, M. Tobo et al., “Orally active lysophosphatidic acid receptor antagonist attenuates pancreatic cancer invasion and metastasis in vivo,” Cancer Science, vol. 103, no. 6, pp. 1099–1104, 2012. View at: Publisher Site | Google Scholar
  145. S. M. Schleicher, D. K. Thotala, A. G. Linkous et al., “Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature,” PLoS One, vol. 6, no. 7, article e22182, 2011. View at: Publisher Site | Google Scholar
  146. N. Euer, M. Schwirzke, V. Evtimova et al., “Identification of genes associated with metastasis of mammary carcinoma in metastatic versus non-metastatic cell lines,” Anticancer Research, vol. 22, no. 2A, pp. 733–740, 2002. View at: Google Scholar

Copyright © 2017 Silvia Anahi Valdés-Rives and Aliesha González-Arenas. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

2184 Views | 820 Downloads | 23 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.