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Abstract

Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1–6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

Keywords

Autotaxin/ENPP2 lysophosphatidate lysophosphatidate receptor cancer pathophysiology cancer therapy pancreatic cancer

Introduction

The incidence of pancreatic cancer is increasing annually, especially in industrialized countries.¹ Despite ever-increasing research efforts over the past few decades, the prognosis of pancreatic cancer remains the poorest among all cancers. It is also one of the leading causes of cancer-related mortality in developed countries, with 6-month median survival time and 5% less 5-year overall survival rate.^1,2 Conventional therapies, such as surgery, radiation therapy, chemotherapy, and combinations of them, have had a limited impact on the course of this aggressive neoplasm, which is characterized by rapid metastasis and resistance to these therapies.³ There is therefore an urgent need to demonstrate the molecular mechanisms driving the development and progression of pancreatic cancer, in order to identify some novel therapeutic targets that will contribute to the development of effective treatment strategies. One such mechanism that has received adequate attention in recent years is the autotaxin/lysophosphatidate (ATX/LPA) axis, because increasing evidence shows that the ATX/LPA axis plays critical roles in numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell (CSC), tumor microenvironment, and treatment resistance.^4–7 Some promising studies are underway to access the therapeutic potential of ATX inhibitor and/or lysophosphatidate receptor (LPAR) antagonists.⁸ Here, the authors review current studies, focusing on the impact of the ATX/LPA axis in pancreatic cancer and the potential use of targeting the ATX/LPA circuits on pancreatic cancer therapy.

ATX/LPA axis

ATX—the major enzyme responsible for LPA production

ATX is a type II ectonucleotide pyrophosphatase/phosphodiesterase (ENPP2) encoded by the ENPP2 gene on chromosome 8 at position 8q24.1, which was originally identified as an “autocrine motility factor” for tumor cell from the melanoma cell line A2058 in 1992 and characterized as a 125-kDa secreted glycoprotein composed of 915 amino acids, which is termed ATXα.^4,9 A few years later, a second isoform was isolated and cloned by the same team from the teratocarcinoma cell line Ntera2D1, now frequently referred to as ATXβ or teratoma ATX, which is the most abundant isoform and the same variant responsible for plasma lysophospholipase D (Lyso PLD) activity.⁴ The third ATX variant was detected for the first time in the rat brain and was originally designated as a brain-specific phosphodiesterase, which is termed as ATXγ.¹⁰ To date, five different alternatively spliced isoforms of ATX have been identified, including α, β, γ, δ, and ε, and all of them are catalytically active.¹¹ Full-length ATX is synthesized as a pre-proenzyme and is secreted by the classical secretory pathway.¹² Although no obvious differences in the core mechanism of involvement in catalysis or physiological activities between different ATX variants have been reported, the differences in gene organization, tissue distribution, and biochemical characterization have been documented.¹³ For instance, the first identified isoform, ATXα, exhibits the lowest expression levels of all isoforms in both the central nervous system and periphery, owing to its unstability.¹⁴ ATXβ originally cloned from teratocarcinoma cells and showed to be identical to plasma Lyso PLD that produces physiologically active LPA is the most abundant isoform in the periphery in both mice and humans.¹⁵

The regulatory mechanisms that control the expression of ENPP2 have not been completely clear. Kawagoe et al.¹⁶ pinpointed that the ATX promoter region located 254 nucleotides upstream of the initiation codon capable of binding transcription factors, and they found that the ENPP2 gene is devoid of typical TATA or CAAT motifs at the 5′ region but contains putative binding sites for other transcription factors, such as Sp1, AP1, and HNF3B. In addition, another study showed that transcription factors AP1 and Sp3 regulated ATX expression through binding to CRE/AP-1-like element at position −142 to −149 and GA box at position −227 to −235 relative to the ATX translational start site.¹⁷ Recent work from Shoshan et al.¹⁸ shows that the ATX gene (ENPP2) promoter contains two consensus binding sites for nuclear factor of activated T cell (NFAT1, NFATC2) proteins, which is a family of transcription factors involved in immune response and metastasis. They demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the ATX gene (ENPP2). A recent research in dedifferentiated soft tissue liposarcomas shows that ATX gene (ENPP2) transcription may be upregulated by c-Jun activity, and which has been associated with increased disease aggressiveness.¹⁹ In addition, a more recent study suggests that both LPA and S1P could inhibit ATX gene expression via a phosphoinositide 3-kinase (PI3K)-dependent inhibitory feedback loop. They demonstrate a new concept that accumulation of LPA in the circulation decreases ATX production; however, this feedback regulation can be overcome by the inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 1β.²⁰

Lyso PLD purified from human plasma¹⁵ or fetal bovine serum²¹ has been shown to be identical to ATX, which catalyzes the production of the bioactive phospholipid mediator LPA from lysophosphatidylcholine (LPC), a lysolipid present at high concentration in plasma and other tissues. Work undertaken by two independent research groups revealed that ATX heterozygote knockout mice show half-normal ATX activity and plasma LPA levels compared with wild-type mice.^22,23 Both conditional gene knockout in adipose tissue and global Enpp2 heterozygosity result in up to 90% decrease in ATX levels or activity in plasma and 38% reduction in plasma LPA levels, indicating that circulating ATX is predominantly produced in adipose tissue and further that it is the primary enzyme responsible for maintaining circulating LPA levels.²⁴ Gierse and colleagues²⁵ have shown that orally, ATX inhibitor provided >95% reduction of LPA levels in plasma. Another study revealed that a novel highly potent ATX inhibitor produces prolonged decreases in plasma LPA formation in vivo, indicating that ATX is the major enzyme responsible for LPA production. For this reason, ATX-mediated LPA production and signal transduction by LPARs is commonly referred to as the ATX/LPA axis.

LPA and LPAR

LPA, one of the simplest natural phospholipids, consisting of a single acyl chain, a glycerol backbone, and a free phosphate group, is one of the major active constituents of serum. Unlike most phospholipids, LPA is also water soluble.²⁶ The majority of extracellular LPA is thought to be generated through three main pathways: (1) cleavage of choline from LPC mediated by Lyso PLD known as ATX in blood; (2) hydrolysis of the fatty acid moiety from the membrane-derived phosphatidic acid (PA) through phospholipase A1 (PLA1) and A2 (PLA2) in inflammatory cells, activated platelets, endothelial cells, and cancer cells; and (3) non-enzymatic, mild oxidation of low-density lipoprotein.¹⁵ As a main membrane-derived multifunctional lipid mediator, LPA is best known for its ability to stimulate proliferation, migration, and survival of both normal and malignant cells.²⁷ LPA signals via a family of G-protein-coupled receptors (GPCRs; also known as LPARs) to initiate its diverse range of cellular actions, which involves a variety of developmental, physiological, and pathophysiological processes, including tumorigenesis and progression.^27–30

LPA binds to and activates at least six specific G-protein-coupled, seven-transmembrane domain receptors, referred to as LPA receptor 1–6 (LPA1–6). LPA1–3 belong to the endothelial differentiation gene (Edg) subfamily, also named as Edg2, Edg4, and Edg7, which have high sequence homology.^7,31 Besides the Edg/LPARs, LPA4 and LPA5 belong to the purinergic subfamily, also named as GPR23 and GPR92, respectively.^32,33 In 2007, the orphan GPC receptor GPR87 was deorphanized and identified as a novel LPAR, named as LPA6.³⁴ The novel non-Edg subgroups of LPARs are structurally distant from the Edg receptors, and the homology among themselves is also low.^33,35

Role of ATX/LPA axis in physiology and cancer pathophysiology

Physiological functions of ATX/LPA axis

ATX is wildly expressed in multiple tissues, with the highest messenger RNA (mRNA) levels detected in the nervous system, placenta, ovary, intestine, and high endothelial venules, with the moderate expression levels in the kidney, prostate, testis, colon, lung, and pancreas.^4,36,37 ATX activity has also been detected in various biological fluids, including cerebrospinal fluid, plasma, serum, peritoneal fluid, and so on.³⁶ The origin of plasma ATX remains to be determined, but most likely sources are adipose tissue, which expresses and secrets ATX at a high level. Indeed, adipose-specific deletion of ATX led to 90% reduction in plasma ATX.²⁴ All biological functions of ATX are thought to be attributable to LPA production and subsequent receptor stimulation.³⁰

LPA of extracellular synthesis is secreted by activated platelets, fibroblasts, tumor cells, some inflammatory cells, nerve cells, injury cells, endothelial cells, etc. The LPA homeostasis is regulated mainly via the LPA-synthesizing enzyme ATX and the LPA hydrolytic enzyme lipids phosphate phosphohydrolases (LPPs).^7,35 The widespread activity of LPA depends on the expression patterns and selective activation of six cognate LPARs.

Owing to various expression patterns, selective activation, and diverse downstream effectors, LPAR1–6 present a wide range of biological effects.³⁸ Ranging from 39 to 42 kDa, the LPARs are coupled to various α-subunits of heterotrimeric G-proteins, such as Gq (LPAR1-5), Gi (LPAR1-3,6), and G12/13 (LPAR1-2,4-6). Via activation of these G-proteins, LPARs mediate the activations of many crucial ubiquitous signaling pathways, thereby regulating the activity of downstream effectors, including adenylyl cyclase, cAMP, intracellular Ca²⁺, mitogen-activated protein kinases (MAPKs), phospholipase C, PI3K/Akt, and small GTPase (Ras, RhO, Rac).³²

The expression of LPAR1 is widespread, and it exerts its effects mainly via activation of MAPK, PI3K/Akt, RhO pathways, and so on. Ligand-dependent activation of LPAR1 mediates cell proliferation, survival, and migration.^31,32 Compared to LPAR1, LPAR2 expression is limited in humans, with high expression in the testes and leukocytes, and moderate expression in the prostate, spleen, thymus, and pancreas. LPAR2 activation is associated with cell survival and migration via initiating signaling cascades, including Ras, Rac, MAPK, PI3K/Akt, and RhO.³⁹ The expression of LPAR3 has been observed in the human heart, testis, lung, prostate, pancreas, ovary, and brain.⁴⁰ LPAR3 can couple with Gq and Gi to mediate LPA-dependent PLC activation, cAMP inhibition, and activation of MAPK but cannot couple with G12/13, and therefore, it does not mediate cell rounding in which G12/13 and RhO are involved.⁴¹ Despite its widespread expression, few studies have linked LPAR3 activity to pathology; LPAR3 knockout mice are viable and grossly normal, only showing a few phenotypic abnormalities such as defects in the immune system and reproductive problems in female mice.⁴² LPAR4 is widely distributed with high expression levels in the brain, platelets, adipose tissue, ovary, uterus, and placenta.⁴³ LPAR4 induces morphological changes such as cell rounding and stress fiber formation via G12/13 and RhO pathways.⁴⁴ LPAR4 has a suppressive effect on cell motility based on the result that LPAR4 knockout genotype enhances LPA-induced migration in mouse embryonic fibroblasts.⁴⁵ LPAR5 is expressed in the heart, placenta, brain, dorsal root ganglia, small intestine, spleen, intestinal CD8⁺ lymphocytes, and B cells. LPAR5 is thought to be involved in nociception via increasing intracellular calcium levels in the dorsal root ganglia through activation of Gq.⁴⁶ In addition, LPAR5 has shown to be involved in immunological function, neurite retraction, and stress fiber formation by coupling to Gα12/13.⁴³ Few detailed studies about LPAR6 have been carried out. One recent study suggested that LPAR6 is an LPAR essential for human hair growth.⁴⁷ Another role of LPAR6 is as a regulator of vascular permeability suggested by high expression in human umbilical vein endothelial cells.⁴⁸

ATX is a vital enzyme that is essential for early embryological development.⁴⁹ ATX homozygous knockout embryos die in utero on average at day 9.5 due to vascular and neural tube defects; ATX heterozygous knockout mice are viable, but they will develop pulmonary hypertension owing to hyper-response to hypoxia-induced vasoconstriction and remodeling. These illustrate the importance of the ATX–LPA axis in vascular and neural development.^22,23 In adult life, ATX is highly expressed in adult neuronal tissues and plays critical roles in maintaining proper neuronal development and function. Physiologically, the most important role of the ATX–LPA axis after birth is probably in wound healing and tissue remodeling. Besides the nervous system, fibroblasts have the second highest expression of ATX mRNA. When tissues are damaged and/or necrose, the ATX/LPA axis could potently activate platelet aggregation and stimulate the growth and migration of fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes.⁵⁰ Steady-state ATX is expressed in only limited tissues, including high endothelial venules in lymph nodes and other secondary lymphoid tissues. However, inflammation signals can upregulate the expression of ATX in various tissues. Some studies show that the ATX/LPA axis mediates lymphocyte extravasation, which is essential for maintaining immune homeostasis. It seems apparent that the ATX/LPA axis emerges as a novel regulator of lymphocyte homing and inflammation.^37,51

Role of ATX/LPA axis in cancer pathophysiology

Aberrant ATX/LPA axis has been associated with multiple signaling pathways including inflammation and carcinogenesis. Studies about metabolism and adipogenesis indicate that ATX and downstream LPA participate in energy homeostasis and obesity control, dysregulation of which can lead to inflammation and carcinogenesis.^36,37 Emerging data indicate that the ATX/LPA axis is implicated in fueling many inflammatory diseases, including asthma, pulmonary fibrosis, rheumatoid arthritis, obesity, atherosclerosis, neuropathic pain, hepatitis, and inflammatory bowel disease.^37,51 It was generally acknowledged that neoplastic diseases often arise at sites of persistent inflammation and several inflammatory conditions, and overwhelming evidence indicates that altered ATX/LPA axis leads to tumorigenesis and progression through the modulation of multiple hallmarks of cancer pathobiology.^{4–7,27–29,37,52} This section will focus on the roles of the ATX/LPA axis in cancer pathophysiology (Figure 1).

Figure 1.

The critical role of ATX/LPA axis in cancer pathophysiology: ATX catalyzes the formation of LPA from LPC. LPA initiates a diverse range of pathological processes (including tumorigenesis and progression) via a number of specific GPCRs (LPARs).

Expression of ATX/LPA axis in cancer

Increased ATX expression has been reported in various types of cancer, such as glioblastomas,⁵³ hepatocellular carcinoma,⁵⁴ thyroid carcinoma,⁵⁵ breast cancer,^56,57 renal carcinoma,⁵⁸ melanoma,⁵⁹ colorectal cancer,⁶⁰ prostate cancer,⁶¹ non-small-cell lung cancer,⁶² and pancreatic cancer.⁶³ In addition, genomic alterations in ATX have been observed across multiple cancers. Information obtained from the Cancer Genome Atlas (TCGA) data shows that most of the genomic alterations are ENPP2 amplifications, which could potentially elucidate dysregulation of ATX/LPA-mediated signaling pathways in various cancers. ATX overexpression or hyperactivation not only predisposes to tumorigenesis but also contributes to other key aspects of tumor biology including metastatic progression. In breast cancer, there was a positive correlation between the expression of nuclear pStat3 and ATX, and inhibition of pStat3 or reducing Stat3 expression led to a decrease of ATX expression levels. These observations suggested that activated Stat3 could regulate the expression of ATX.⁶⁴ The tumorigenesis in the liver is usually related to inflammation such as hepatitis B and C; ATX was proven to play a crucial role in this transformation process. Besides, inflammatory TNF-α/NF-kappaB axis could promote ATX expression and secretion.⁵⁴ Therefore, the mechanism regulating ATX expression is complex and has not been fully understood.

LPA is predominantly and continuously produced in blood from LPC through the plasma ATX; determination of LPA or ATX concentrations in human samples, especially plasma, may be clinically relevant and important for diagnostic purposes. Compared to LPA, serum ATX antigen is stable, the preparation of clinical samples for this ATX measurement is easy, and its level is closely correlated to the LPA concentration. Therefore, the ATX assay seems to be promising for laboratory testing.⁶⁵ In fact, the ATX levels are significantly increased in B-cell neoplasms (especially follicular lymphoma),¹¹ hepatocellular carcinoma,⁶⁵ and hypoalbuminemia conditions.⁶⁶ In another recent study, ATX activity and gene expression were significantly elevated in patients with thyroid carcinoma compared to other groups. Higher levels of ATX activity and gene expression were significantly correlated with larger tumor size and undifferentiated pathological subtype in thyroid carcinoma. It indicated that ATX activity and gene expression were a reliable diagnostic tool and prognostic marker in thyroid carcinoma.⁵⁵

Functional implications of ATX/LPA axis in cancer cell proliferation

LPA acts through the cell surface GPC receptor (GPCR, i.e. LPAR1–6) to elicit a wide range of cellular responses, which include promoting cell proliferation and motility as well as increasing cell survival. In human ovarian cancer, the dual effects were probably involved. The indirect mechanism was that LPA promoted angiogenesis and then stimulated tumor cell proliferation via vascular endothelial growth factor (VEGF). The direct mechanism was that LPA directly increased the level of cyclin D1 in ovarian cancer cells.⁶⁷ In recent years, emerging evidences showed that LPA also stimulated ovarian cancer cell proliferation and motility via MAPK, CXCL12-CXCR4 axis, TAZ (transcriptional co-activator with PDZ binding motif), and its downstream signaling pathways.⁶⁸ Sphingosine kinases 1 (SphK1), one kinase of S1P production, is overexpressed in many types of cancers. It has been reported that crosstalk between LPA/LPA1 and epidermal growth factor receptors (EGFRs) mediated the upregulation of SphK1 to promote cell proliferation and motility in gastric cancer cells and squamous cell carcinoma cell lines of the head and neck.⁶⁹ Both hypoxia-inducible factor 1α (HIF1α) and P53 are pivotal regulators of tumor cell growth and survival. In a recent research about colon cancer, the authors suggested that LPA induced proliferation of colon cancer cells through upregulation of HIF1α by dynamically modulating its interaction with KLF5 and P53.⁷⁰ Another research about colon cancer found that LPA stimulated proliferation of colon cancer cells by activation of β-catenin through multiple pathways involving phosphorylation of GSK-3 and β-catenin, and enhancing β-catenin interaction with TCF4, which could be enhanced by KLF5 via increasing the β-catenin–TCF4 interaction.⁷¹ ATX has been reported to act as a motility and growth factor in a variety of cancer cells, and has important functions in cell migration and proliferation. During hematopoiesis, the production of bioactive LPA through ATX was involved in controlling proliferation and migration, and deregulation of ATX contributes to the pathogenesis of acute myeloid leukemia.⁷² The short hairpin RNA (shRNA) targeting ATX down-regulates endogenous ATX expression in human gastric cancer cells and inhibits their proliferative, migratory, and invasive potential.⁷³ It was already clear that ATX induced cell proliferation and motility driven by LPA1 activation, and downstream Rac-1 activation played a crucial role in LPA1-mediated cell proliferation and motility.⁶⁹

Functions of ATX/LPA axis in tumor angiogenesis, migration, invasion, and metastasis

ATX/LPA axis hyperactivation not only predisposes to tumorigenesis but also contributes to other critical aspects of cancer biology including angiogenesis, migration, invasion, and metastasis.⁴ Emerging evidences demonstrated that ATX/LPA promotes cells motogenic activity in diverse types of tumors including ovarian,⁷⁴ breast,⁵⁶ hepatocellular,⁵⁴ melanoma,⁷⁵ gastric,⁷⁶ bladder,⁷⁷ oral squamous,⁷⁸ and pancreatic⁷⁹ cancer cell lines. Through generating transgenic mice that expressed wild-type human ATX or LPAR driven by MMTV-LTR, the aberrant expression of ATX or LPAR in mammary glands was sufficient to induce the initiation and progression of breast cancer.⁵⁷ In another vitro study, inhibition of ATX production or activity could block LPC-induced migration of human breast cancer and melanoma cells.⁷⁵ The possible mechanisms include RhoA/ROCK/MMPs pathways,⁸⁰ PI3K/ZEB1/oncomiR-21,⁸¹ beta-arrestin/Ral signaling,⁸² binding to integrins,⁸³ and so on. Furthermore, studies from different teams suggested that platelet-derived ATX also could control metastasis of breast cancer cells to bone, similar to tumor-derived ATX.⁸⁴

It has been a consensus that the classic LPARs (LPAR1–3) were involved in tumor angiogenesis, migration, invasion, and metastasis.^{67,77,82,85,86} The mechanisms include induction of VEGF expression,⁶⁷ promotion of uPA expression,⁸⁶ and activation of Ras/Raf-MAPK, G12/13-Rho-RhoA, PI3K-AKT/PKB,⁸⁷ beta-arrestin/Ral,⁸² Gq11/p38,⁸⁵ PKC/alpha-CARMA3,⁸⁶ and EGFR⁷⁸ signaling pathways. In contrast to motility-stimulation of LPAR, Lee et al.⁴⁵ provided genetic and biochemical evidences that LPAR4 was a suppressor of LPA-dependent cell migration and invasion; they found that LPAR4 attenuated LPAR1-driven migration and invasion, indicating functional antagonism between two subtypes of LPAR. Similarly, Matayoshi et al.⁸⁸ found that LPAR4 negatively modulated the malignant behavior of head and neck squamous cell carcinoma cells. A study in pancreatic cancer shows that LPAR 4, 5, 6 have the diverse effects on the activation of tumor progression; they demonstrated that LPAR4 and LPAR5 negatively and LPAR6 positively regulated the malignant properties in pancreatic cancer cells.⁸⁹ A recent research suggested that LPAR5 exerts an anti-invasive action in melanoma cells; host LPAR5 promotes melanoma-derived invasion and lung metastasis.⁵⁹ These findings implicated that tumor and stromal LPAR might play different roles in invasion and the seeding of metastasis. In a study about prostate cancer, authors showed that enhanced LPAR6 signaling promoted migration of androgen-independent prostate cancer cells, and knockdown of LPAR6 actually caused the opposite effect.⁹⁰

Role of ATX/LPA axis in the resistance to anti-cancer therapies

Effective chemotherapy and radiotherapy principally depend on successful induction of apoptosis, and defects in apoptotic signaling are a major cause of therapeutic resistance. It has been reported that the ATX/LPA signaling axis might protect and rescue various cancer cells from chemo- and radiotherapy-induced apoptosis, and also be well known to mediate resistance to chemotherapy- and radiation-induced cell death.^6,91 One study from earlier stage found that LPA could protect and rescue intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis through the inhibition of caspase-3/CPP32 activation via LPAR1 and LPAR2.⁹² Another study demonstrated that ATX could protect breast cancer cells against Taxol-induced apoptosis via converting extracellular LPC into LPA.⁹¹ The subsequent study suggested that the basis of such antagonistic action of ATX/LPA was releasing breast cancer cells from Taxol-induced mitotic arrest.⁹³ Vidot et al.⁹⁴ reported that ATX delayed apoptosis induced by carboplatin in ovarian cancer cells through synthesis of survival factor LPA; in contrast, the functional blockage of ATX (siRNA targeting ENPP2 or small molecule inhibitors) could accelerate apoptosis induced by carboplatin. Another research revealed that endothelial ATX promoted renal tumorigenesis through LPA signaling, and it was functionally involved in the acquired resistance of renal cell carcinoma to sunitinib. The coadministration of inhibitor to the ATX/LPA axis with sunitinib would prolong the sensitivity of renal cell carcinoma to sunitinib in the xenograft model.⁶⁸ A recent research has shown that LPA signaling increased Nrf2 transcription factor stability and nuclear localization, and further increased transcription of multidrug-resistant transporters and antioxidant genes, which protected cells from chemotherapy-induced death.⁹⁵ In recent years, the role of the ATX/LPA axis in cancer resistance to radiotherapy has also emerged.⁶ It has been reported that inhibition of cytosolic phospholipase A2 (cPLA2), an upstream factor of ATX and LPA, coordinated with radiotherapy notably delayed tumor growth compared to radiotherapy alone, and identified cPLA2 as a molecular target to enhance the therapeutic ratio of radiation in ovarian cancer.⁹⁶ Another study also demonstrated that inhibition of the ATX/LPA axis might significantly improve malignant glioma response to radiation therapy, and identified the ATX/LPA axis as a molecular target for the development of radiosensitizer for glioma.⁹⁷ Altogether, these data indicated that blocking ATX/LPA signaling might provide a novel strategy for improving chemotherapy and radiotherapy.

The critical roles of ATX/LPARs axis in pancreatic cancer

Aberrant activation of the ATX/LPARs axis has been observed in a series of human malignancies.^7,52,61,62 Elevated expression of LPA was a property of activation of the ATX/LPARs axis. It has been reported that the levels of LPA were significantly increased in pancreatic cancer patients’ serum and ascites.^98,99 By binding to its receptors and activation of its downstream signaling pathways, such as PI3K/AKT, RAS/ERK, and Rho and Hippo, LPA promoted pancreatic cancer cell proliferation, migration, and invasion.^100,101

The expression of ATX/LPARs axis in pancreatic cancer

Although the direct evidence of ATX expression in pancreatic cancer tissue has not been reported, Houben and Moolenaar²⁷ analyzed multiple data sets of microarrays and showed that the expression of ATX was elevated, especially in pancreatic cancers.¹⁰² Furthermore, Nakai et al.¹⁰² evaluated the clinical significance of serum ATX level in gastrointestinal cancer (including esophagus cancer, stomach cancer, colorectum cancer, biliary tract cancer, and pancreatic cancer) and found that increased serum ATX activity was predominantly discovered in pancreatic cancer patients when compared with chronic pancreatitis or pancreatic cysts. These studies indicated that serum ATX activity might be a useful marker for identifying pancreatic cancer. However, the mechanisms of enforced ATX expression in pancreatic cancer have not been investigated. In hepatocarcinoma cells, TNF-α upregulated ATX via its downstream target NFκB. In Wilms’ renal tumors, the increased expression of ATX was correlated to the activation of Wnt/β-catenin pathway or the expression level of v-jun in transformed fibroblasts. In thyroid carcinoma cells, EGF and b-FGF led to the upregulation of ATX expression.⁵⁴ In pancreatic cancer, TNF-α, NFκB, Wnt/β-catenin pathway, v-jun, EGF, and b-FGF were also aberrantly expressed or activated; thus, the above studies gave us a clue to further investigate the mechanism of increased expression of ATX in pancreatic cancer.

LPAR1–3 belong to classic GPCRs and LPAR4–6 are of the purinergic receptor family. Here, LPAR1–3 are the predominant receptors of LPA. In pancreatic cancer, Gong et al.¹⁰³ evaluated the expression of LPAR1–3 in 50 Chinese pancreatic cancer patients via real-time polymerase chain reaction (PCR). There were no significant differences in LPAR1 expression between tumor and adjacent non-tumor tissues, and LPAR3 was weakly expressed in both tumor and adjacent non-tumor tissues, but the expression of LPAR2 was significantly increased in tumor tissues as compared with non-tumor tissues. Although this study analyzed the mRNA levels of LPAR1–3 in a relatively large number of pancreatic cancer tissues, the protein levels of LPAR1–3 in pancreatic cancer tissues need further investigation. The mechanisms of increased expression of LPARs in pancreatic cancer warrants further study. The expression of LPAR4–6 and the mechanisms of increased expression of LPARs have not been revealed in pancreatic cancer.

Role of ATX in pancreatic cancer

It has been reported that in RAS-mutated NIH3T3 murine fibroblasts, overexpression of ATX led to elevated tumor development and invasiveness as compared with control groups. Furthermore, increased ATX expression in the mammary gland of MMTV-ATX transgenic mice led to the development of spontaneous breast tumors and metastasis formation.⁵⁷ These studies suggested that ATX had oncogenic and pro-metastatic properties. There was no ATX transgenic mouse of pancreas till now; however, treated rats or pancreatic cancer cell lines with chemicals (such as Testosterone), which could induce pancreatic tumors, led to increased protein levels of ATX.⁶³ These results suggested that ATX was a target for chemicals which promoted pancreatic tumor development, and also indicated that ATX might function as an oncogene during pancreatic cancer tumorigenesis. Furthermore, the increased serum and ascites levels of LPA, which induced cancer cell proliferation, migration, and invasion in pancreatic cancer patients also suggested that the activity of ATX was elevated and promoted pancreatic cancer development and progression.^79,104,105 The mechanisms of the ATX/LPA axis promoting pancreatic cancer development and progression were complicated and not fully revealed. Liao et al.’s⁹⁹ study suggested that LPA led to phosphorylation of tyrosine in focal adhesion kinase (FAK) and paxillin, and contributed to increased cell motility of PanC-1 cells. In Gardner et al.’s⁹⁸ study, LPA promoted pancreatic cancer cell invasive migration via Galpha13, and a dominant-negative mutant of Galpha13 or siRNA targeting Galpha13 could disrupt the effect of LPA. In Lv et al.’s⁷ study, LPA promoted the glycolytic phenotype of pancreatic cancer via regulating the expression of hexokinase-2. Furthermore, the ATX/LPA axis stimulated DNA synthesis, proliferation, and migration of pancreatic cancer cells via GPCRs/ERK1/2 and Rho pathways.^104,105 However, further studies are needed to investigate the roles and mechanism of ATX in pancreatic cancer development and progression.

Role of LPARs in pancreatic cancer

ATX catalyzes the synthesis of LPA, and LPA exerts its biological effect by binding to its specific receptors LPAR1–6. By binding to their ligand LPA, LPARs exert different functions in pancreatic cancer development and progression. In an in vivo study, Ki16198, inhibitor of LPAR1 and LPAR3, significantly inhibited YAPC-PD pancreatic cancer cell–inoculated nude mice tumor growth and attenuated invasion and metastasis to liver, lung, and brain. Mechanism studies revealed that Ki16198 decreased the expression of LPA-induced matrix metalloproteinases (MMPs).¹⁰⁶ In vitro study, Ki16198 and VPC12249, both were antagonists for LPAR1 and LPAR3, but not an LPAR3-selective antagonist attenuated the stimulated effect of ascites and LPA on pancreatic cells motility. Furthermore, the mRNA level of LPAR1 in pancreatic cancer cells with high migration activity to ascites was much higher than in cells with low migration activity, and LPAR1 siRNA significantly abolished the migration response to ascites and LPA.⁷⁹ These results indicated that LPA was an essential component of ascites and that LPAR1 played a critical role in mediating the promoting functions of LPA in pancreatic cancer growth, invasion, and migration. However, the study of Gong et al.¹⁰³ reported that the mRNA levels of LPAR2, but not LPAR1 or LPAR3, were significantly increased in pancreatic cancer tissues when compared with non-cancer tissues. Since this study only analyzed the mRNA levels of LPAR1, 2, and 3, which might not fully represent the expression levels of LPAR1, 2, and 3, respectively, further studies are needed to demonstrate the expression and function of LPAR1, 2, and 3 in pancreatic cancer development and progression. In a recent study, the authors reported that active Yes-associated protein (YAP) promotes pancreatic cancer cell motility, invasion, and tumorigenesis in a mitotic phosphorylation-dependent manner through LPAR3.¹⁰⁰

LPAR4, 5, and 6 belong to the purinergic receptor family, and the studies of the expression and function of LPAR4, 5, and 6 in pancreatic cancer are limited. Ishii et al.,⁸⁹ in their study, generated LPAR4, 5, and 6 knockdown cells from PANC-1 and analyzed the cellular functions of those cells. They found that knockdown of LPAR4 and 5 enhanced the cell motility, invasion, and colony formation, and the supernatants from the shRNA-transfected PANC cells significantly induced the cell motility and tube formation of endothelial cells. But knockdown of LPAR6 got the opposite results. This study revealed that LPAR4 and 5 might be tumor suppressors, whereas LPAR6 functioned as an oncogene in pancreatic cancer cells. However, more studies are needed to investigate the expression and confirm the roles of LPAR4, 5, and 6 in pancreatic cancer development and progression.

Expert opinion

ATX-mediated LPA production and signal transduction via LPARs is commonly referred to as the ATX/LPA axis, which participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer. Overwhelming evidences indicate that the ATX/LPA signaling axis plays key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, CSC, tumor microenvironment, and treatment resistance by interacting with a series of LPARs. Moreover, the mechanisms involved in the ATX/LPAR axis regulating tumorigenesis and progression have gotten adequate attention in recent years.

It has been proven that ATX was identical to plasma Lyso PLD, which is the major enzyme responsible for LPA production. LPA as a main membrane-derived multifunctional lipid mediator is best known for its ability to stimulate proliferation, migration, and survival of both normal and malignant cells.²⁷ LPA initiates its diverse range of cellular actions via binding to and activating at least six specific G-protein-coupled, seven-transmembrane domain receptors, referred to as LPA receptor 1–6 (LPA1–6).

Aberrant ATX/LPA axis has been associated with multiple signaling pathways linking to inflammation and cancer. Increasing evidences indicate that altered ATX/LPA axis leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology, including cell proliferation, tumor angiogenesis, migration, invasion, metastasis, and resistance to anti-cancer therapies.

Elevated expression of LPA was a property of activation of the ATX/LPARs axis. It has been reported that the levels of LPA were significantly increased in pancreatic cancer patients’ serum and ascites. However, further studies need to be conducted to analyze aberrant expression of ATX and LPARs in pancreatic cancer. In addition, the mechanisms by which the ATX/LPA axis promotes pancreatic cancer development and progression were complicated and not been fully revealed.

In conclusion, the ATX/LPA axis appears to play a critical role in pancreatic cancer, and inhibition of this signaling, such as inhibition of ATX, blocking of LPAR, or downstream signaling, may represent an effective therapeutic approach or could be used as an adjuvant therapy to improve the efficacy of traditional anti-cancer treatment.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This work was supported by grant 81120108017 and 81572951 from the National Natural Science Foundation of China (to Qian Huang), 81502043 from the National Natural Science Foundation of China (to Ming Quan), 81502018 from the National Natural Science Foundation of China (to Jiujie Cui).

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The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

Abstract

Keywords

Introduction

ATX/LPA axis

ATX—the major enzyme responsible for LPA production

LPA and LPAR

Role of ATX/LPA axis in physiology and cancer pathophysiology

Physiological functions of ATX/LPA axis

Role of ATX/LPA axis in cancer pathophysiology

Expression of ATX/LPA axis in cancer

Functional implications of ATX/LPA axis in cancer cell proliferation

Functions of ATX/LPA axis in tumor angiogenesis, migration, invasion, and metastasis

Role of ATX/LPA axis in the resistance to anti-cancer therapies

The critical roles of ATX/LPARs axis in pancreatic cancer

The expression of ATX/LPARs axis in pancreatic cancer

Role of ATX in pancreatic cancer

Role of LPARs in pancreatic cancer

Expert opinion

Footnotes

Declaration of conflicting interests

Funding

References