Review
Complexities of lysophospholipid signalling in glioblastoma

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Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumour and continues to have a very poor median survival of 12–16 months despite current best therapies. These aggressive tumours always recur after treatment and are defined by their ability to diffusely infiltrate and invade normal brain parenchyma. Autotaxin is overexpressed in GBM, and is a potent chemotactic enzyme that produces lysophosphatidic acid. Lysophospholipid (LPL) signalling is known to increase invasion of solid tumours and is also dysregulated in GBM. The LPL pathway has been shown to interact with known cancer-related signalling pathways, including those for epidermal growth factor and yes-associated protein, which are also dysregulated in GBM. The interactions between these pathways provide insights into the complexities of cancer signalling and suggest potential novel targets for GBM.

Introduction

Glioblastoma multiforme (GBM) is the most malignant (World Health Organization grade IV) glioma and continues to have a very poor median survival of 12–16 months despite current best therapies (maximal safe resection with concurrent temozolomide chemotherapy and radiation therapy) [1]. These aggressive tumours always recur after treatment and are defined by their ability to diffusely infiltrate and invade normal brain parenchyma. Thus the search for targeted agents inhibiting cell proliferation, survival and invasion has intensified. Research into the epidermal growth factor receptor (EGFR) pathway has led to clinical trials of EGFR and phosphatidylinositol-3-kinase (PI3K) inhibitors that modulate cell survival and proliferation in pre-clinical models. However, results from early EGFR inhibitor trials have not delivered on their promise and PI3K inhibitor trials are ongoing [2], [3], [4]. These trials have made it obvious that strategies combining therapies against multiple targets are required to account for the existence of complex pathway interactions and redundancies. For example, matrix metalloproteases (MMP) degrade extracellular matrix components to produce more favourable conditions for cell migration and invasion [5]. However, they also cleave and activate growth factors such as epidermal growth factor (EGF) [6]. The function of integrins and their influence on cell morphology and migration has also been enlightening [7], [8]. More recently, other promising factors have been identified, including autocrine motility factor receptor, heparin-binding epidermal growth factor, ephrin-B3, netrin 4 and autotaxin (ATX) [9]. The latter three are of interest because their role in cell migration and motility in neural stem cells suggests a similar role in glioma-derived cancer stem cells, that have a putative role in GBM progression [10], [11]. ATX in particular is a powerful chemotactic enzyme involved in lysophospholipid (LPL) signalling, and its recent prominence in the literature has highlighted the importance of lipid signalling within complex intracellular pathway interactions. This review focuses on the role that LPL signalling may play in gliomagenesis and its potential as a target in the treatment of this highly malignant disease.

Section snippets

Lysophosphatidic acid

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are the main membrane-derived lipid signalling molecules. LPA has a 3-carbon glycerol backbone, with an attached single acyl or alkyl chain of varying length which imparts some differences in receptor efficacy [12]. Whilst some LPA production may occur intracellularly, much of it is produced extracellularly by secreted enzymes. There are three known pathways: (1) cleavage of LPL (such as lysophosphatidylcholine) by lysophospholipase

LPA receptors

Only a brief review of the LPA receptors will be provided here as there are many other detailed reviews available [12], [16], [22], [23], [24]. At the time of writing, the International Union of Basic and Clinical Pharmacology had recognised six definitive G-protein coupled-LPA receptors (collectively LPAR) designated LPA1–6 (Table 1). Broadly, the receptors fall into two families: endothelial differentiation gene (Edg) and non-Edg (purinergic) receptors [12]. LPA1 (Edg2), LPA2 (Edg4) and LPA3

LPA signalling in cancer

Since Stracke et al. discovered the promotile effects of ATX on melanoma cells in 1992, the LPA pathway has been investigated for its role in tumour invasion and metastasis [36]. However, its original role in nucleotide metabolism could not be directly reconciled with this biological effect. It was the subsequent discovery by Umezu-Goto et al. [14] and Tokumura et al. [15] that ATX had additional lysophospholipase D activity that triggered further interest in LPA. Recent elucidation of the

Discussion

Decades of glioma research are now seeing the beginnings of molecular and genetic profiling of gliomas. Additionally, glioma-derived cancer stem cells have been identified, providing a new framework to investigate this disease’s resistance to treatment and subsequent recurrence. Much of the evidence for the role of LPA in cancer is spread across different cell lineages making it difficult to extrapolate some of the knowledge to gliomas. However, the emerging reports regarding LPA and

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

This study was funded by the Neurosurgical Society of Australasia/LifeHealthCare scholarship (2012) and the Brain Foundation of Australia Brain Tumours Award (2012) and the Victorian State Government’s Department of Innovation, Industry and Regional Development’s Operational Infrastructure Support Program. AP is supported by a National Health and Medical Research Council Career Development Fellowship.

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