Role and Signaling Mechanisms of LPA in Cancer Development

Dear Colleagues,

Lysophosphatidic acid (LPA), a prototype bioactive lipid-signaling molecule, exerts multiple physiological and pathological roles in almost every major organ system and in almost all cell types. In particular, LPA plays important roles in cancer, ranging from tumor initiation to progression, covering all 10 cancer hallmark activities, including but not limited to stimulation of the proliferative signaling, evading growth suppressors and resisting cell death, enabling replicative immortality, inducing angiogenesis and lymphangiogenesis, and activating invasion and metastasis. LPA also affects genome instability, radiation-induced DNA damage repair, stresses including inflammation and mechanical forces, drug resistance, energy metabolism, and metabolic reprogramming. Among these activities, the role of LPA in tumor initiation, cancer stem cells, and in tumor microenvironment, including angiogenesis and in the immune system, has emerged as the newer frontiers in LPA research. 

The broad range of LPA effects mediate a wide range of signaling pathways. LPA signals mainly through the six G protein-coupled receptors LPA_1-6, but it also displays intracellular roles through its nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) signaling, as well as crosstalks between GPCR signaling and essentially all other major classes of membrane receptors, including ligand-gated ion channels, receptor tyrosine kinases (RTKs), receptors with other enzymatic activities (serine or serine/threonine kinases and guanylyl cyclase enzymatic activities), other GPCRs, integrins, cytokine receptors, T- and B-cell receptors, as well as intracellular receptors, such as Src and PPARγ. Downstream signaling pathways cover essentially all major cancer-related signaling pathways, including pathways of Ca²⁺ mobilization, protein kinase C activation, release of arachidonic acid, activation or inhibition of adenylate cyclase, activation of the oncogenic PI3K-AKT, Ras-ERK, Rho-Rock, tumor necrosis factor (TNF)-trail-caspase, Jak-signal transducers, and activators of transcription (Stat) pathways. In particular, the LPA effects on pathways involved in stemness, such as the NF-κB, Wnt-β catenin, NOTCH, Sonic-Hedgehog (Hh), TGFβ-SMAD, ALDH, and Hippo-YAP signaling pathways have gained increased attention in recent years.

LPA is an established oncolipid for multiple cancers. Its potential clinical applications rely on its marker and target values. LPA, LPA rectors, and/or PLA₂/ATX have been shown to be diagnostic and/or prognostic markers for most major forms of cancers, including ovarian, cervical, endometrial, kidney, liver, colon, breast, endometrial, bladder, gastrointestinal, prostate, pancreas, thyroid, brain, and lung, as well as melanoma and hematological malignancies. Strategies of targeting LPA have focused on its metabolic enzymes and its receptors. LPA is produced from secreted enzymes from lysophosphatidylcholine (LPC) by autotaxin (ATX), as well as phospholipase A₂ (PLA₂₎ by either providing the substrate LPC for ATX, or directly producing LPA from phosphatidic acid (PA). LPA is degraded outside cells by a family of enzymes called lipid phosphate phosphatases (LPPs). In particular, the ATX/LPA axis has received increasing interest as a target in cancers, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity, and impaired glucose homeostasis. The crystal structures determined for ATX and several LPA receptors have facilitated the design and development of anti-cancer reagents targeting them. While Food and Drug Administration (FDA)-approved inhibitors against ATX and LPA monoclonal antibody have entered into clinical trials for fibrosis, their applications in cancer have yet to come. The major challenges that we are facing in moving LPA applications from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues. Despite these obstacles, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications.

The primary focus of this Specific Issue will be on the “Role and Signaling Mechanisms of LPA in Cancer Development”, as well as potnetial clinical applications, with emphasis on tumor stem cells, pathways involved in stemness regulated by the ATX-LPA axis, and targeting the ATX-LPA axis in cancer.

Prof. Yan Xu
Guest Editor

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• LPA
• autotaxin (ATX)
• cancer
• initiation
• progression
• cancer stem cell (CSC)