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Page 2 of 24 Saier et al. J Cancer Metastasis Treat 2021;7:43 https://dx.doi.org/10.20517/2394-4722.2021.87

Keywords: Lysophosphatidic acid, sphingosine 1-phosphate, eicosanoids, prostaglandins, leukotrienes, cancer,
bone cells

INTRODUCTION
Bone is a highly dynamically regulated tissue which undergoes continuous homeostatic and reactive
remodeling by the coordinated action of bone cells, namely osteoblasts, osteoclasts, and osteocytes, and
controlled by endocrine factors, immune cells, and mechanical forces. Sir Paget’s “seed and soil” theory was
the first still valid concept explaining why certain types of cancers have remarkably high propensity to form
bone metastases such as breast and prostate cancers . During the 1990s, works released from Greg Mundy’s
[1]
lab led to the development of an additional theory leading to the notion of the “vicious cycle” established at
the sites of bone metastases, reflecting the reciprocal stimulation between tumor growth and bone
[2]
resorption . The vicious cycle theory is also still valid with even more clinical impact, as it is the current
target of the best systemic therapies against bone metastases that use anti-resorptive agents (i.e.,
bisphosphonates and denosumab) . Unfortunately, even under these best standards of care, patients with
[3]
bone metastases still have limited overall survival, indicating the existence of additional molecular
mechanisms. Bioactive lipids are widely present in the organism and affect almost all vital systems. In this
review, we focus on two lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate
(S1P), and two classes of eicosanoids, prostanoids and leukotrienes, because all of these molecules can
regulate cancer progression including bone metastasis as well as important biological processes directly
related to bone such as skeletal development, mineralization, regulation of bone mass and homeostasis,
osteoblast-osteoclast coupling, and bone resorption and formation.

LYSOPHOSPHATIDIC ACID
Structure, synthesis, and receptors
LPA is the simplest phospholipid which is composed of a glycerophosphate backbone linked to a single fatty
acid chain. LPA can be synthesized from two pathways. In the first one, phospholipid precursors such as
phosphatidylcholine (PC), phosphatidylserine (PS), or phosphatidylethanolamine (PE) can be converted to
lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), and lysophosphatidylethanolamine (LPE),
respectively, through the action of phosphatidylserine-specific phospholipase A1 or secretory phospholipase
A2 such as in blood platelets [Figure 1]. LPC appears to be the most abundant LPA precursor in the
[4,5]
blood. These precursors can then be converted to LPA by a lysophospholipase D (LysoPLD). LPA can also
be generated by a distinct mechanism, namely the acylation of glycerol-3-phosphate by glycerophosphate
acyltransferase and the phosphorylation of monoacylglycerol by monoacylglycerol kinase . LPA level is
[6]
tightly tuned by degradation mechanisms mediated by different classes of enzymes such as lipid phosphate
phosphatases (LPPs) or LPA acyltransferase .
[7]
[8,9]
Autotaxin (ATX or ENPP2) is responsible for LPA levels in the blood, as evidenced by LPA concentrations
in serum that are half normal values in Enpp2 heterozygous mice . As a unique member of the family of
[10]
+/-
the seven ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) that hydrolyze pyrophosphate and
phosphodiester bonds in nucleotides and their derivatives , ATX possess a LysoPLD activity, allowing the
[11]
hydrolysis of LPC and other lipid precursors to produce LPA. ATX is present at high concentration in the
blood circulation . However, the origin of ATX in blood remains to be determined. Nevertheless, adipose
[12]
fl/fl
tissue is likely one of the main sources, as revealed in aP2-Cre/Enpp2 mice presenting 30% decrease in
LPA levels in plasma . ATX is also highly expressed in the brain and lymphatic high endothelial
[13]
venules . Although ATX is capable of hydrolyzing nucleotides in vitro, its biological function relies on its
[14]
[15]
lysoPLD activity, as the apparent affinity for LPC is 10 times higher than that of nucleotides and as