Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.

Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special?

“…It is therefore not surprising that the role of LPA in cancer has been closely studied and that LPA antagonists have been developed and tested as therapeutic agents for cancer. The application of LPA antagonists in cancer treatment is reviewed in another article of this Special Issue [1].…”

“…LPA is particularly efficacious at activating Rho [29]. LPARs as potential therapeutic targets and the LPA "axis" in cancer have been reviewed on multiple occasions over the years [1,15,18,20,[30][31][32], including in the current Special Issue [33].…”

Lysophosphatidic acid receptor 6 regulated by miR-27a-3p attenuates tumor proliferation in breast cancer

“…Lysophosphatidic acid (LPA) is a bioactive molecule which participates in many physical and pathological processes, such as brain development, pain, asthma, heart disease, and cancer [ 5 – 9 ]. In cancers, LPA functions as a procancerous substance which, together with corresponding receptors, induces cancer cell proliferation, migration, invasion, angiogenesis, inflammation, and other effects [ 10 , 11 ]. However, there are studies with contradictory findings [ 12 – 14 ]; hence, more studies are needed to ascertain the roles of LPA in cancer with regard to its receptors.…”

“…There are six types of LPA receptors (LPARs; LPAR1-6) which belong to G protein-coupled receptors (GPCRs), characterized by seven transmembrane helices. LPAR1-5 have been well documented; however, LPAR6 is relatively poorly studied [ 11 , 15 ]. LPAR6 was first reported in hypotrichosis simplex [ 16 ] and afterwards was implicated in the initiation and progression of cancer [ 13 , 14 , 17 – 22 ].…”

Phospholipase A1 Member A Activates Fibroblast-like Synoviocytes through the Autotaxin-Lysophosphatidic Acid Receptor Axis

“…LPA mediates its effects through activation of its six receptors LPA1–6. The ATX-LPA receptor axis has been extensively studied in vascular system development [ 26 ], in the regulation of lymphocyte homing [ 27 ], in cancer cell growth and metastasis [ 28 , 29 , 30 ], as well as in the development of cardiovascular diseases [ 31 ]. The sn-1 and the sn-2 positions of phospholipids are usually occupied by saturated and unsaturated fatty acids, respectively [ 32 ].…”