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  • Review Article
  • Published:

The emerging role of lysophosphatidic acid in cancer

Nature Reviews Cancer volume 3, pages 582–591 (2003)Cite this article

Key Points

  • Lysophosphatidic acid (LPA) is a serum phospholipid with growth-factor-like activities for many cell types. It acts through specific G-protein-coupled receptors on the cell surface.

  • LPA stimulates cell proliferation, migration and survival. In addition, LPA induces cellular shape changes, increases endothelial permeability and inhibits gap-junctional communication between adjacent cells. LPA promotes wound healing in vivo and suppresses intestinal damage following irradiation.

  • LPA receptors couple to multiple signalling pathways that are now being clarified. These pathways include those initiated by the small GTPases RAS, RHO and RAC, with RAS controlling cell-cycle progression and RHO/RAC signalling having a dominant role in (tumour) cell migration and invasion.

  • Significant levels (>1 μM) of bioactive LPA are detected in various body fluids, including serum (but not plasma), saliva, follicular fluid and malignant effusions. The mechanisms by which bioactive LPA is produced were unknown until recently.

  • Recent evidence shows that LPA is produced extracellularly from lysophosphatidylcholine by 'autotaxin' (ATX/lysoPLD). ATX/lysoPLD is a ubiquitous exo-phosphodiesterase that was originally identified as an autocrine motility factor for melanoma cells and is implicated in tumour progression. Through local production of bioactive LPA, ATX/lysoPLD might support an invasive microenvironment for tumour cells and therefore contribute to the metastatic cascade.

  • Both LPA receptors and ATX/lysoPLD are aberrantly expressed in several cancers.

  • The use of inhibitory drugs directed against LPA receptors and/or ATX/lysoPLD could be effective in suppressing tumour metastasis.

Abstract

The bioactive phospholipid lysophosphatidic acid (LPA) stimulates cell proliferation, migration and survival by acting on its cognate G-protein-coupled receptors. Aberrant LPA production, receptor expression and signalling probably contribute to cancer initiation, progression and metastasis. The recent identification of ecto-enzymes that mediate the production and degradation of LPA, as well as the development of receptor-selective analogues, indicate mechanisms by which LPA production or action could be modulated for cancer therapy.

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Figure 1: LPA metabolic pathways.
Figure 2: Major LPA signalling pathways.
Figure 3: Regulation of bioactive LPA.

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Acknowledgements

We would like to thank E. Goetzl (University of California, San Fransisco) as well as members of our laboratories for allowing us to share unpublished data. This work is supported by grants from the National Cancer Institute (USA), Department of Defense (USA) and the Netherlands Cancer Institute (Holland).

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Authors and Affiliations

  1. MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Gordon B. Mills

  2. The Netherlands Cancer Institute, Amsterdam, 1066CX, The Netherlands

    Wouter H. Moolenaar

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DATABASES

Cancer.gov

breast cancer

cervical cancer

endometrial cancer

head and neck

melanoma

myeloma

ovarian cancer

prostate cancer

LocusLink

ATX

LPA1

LPA2

LPA3

LPA4

PLA1

PLA2

PLC

PPARγ

RAS

TIAM1

Glossary

PHOSPHOLIPID

A small molecule with one or two fatty acyl chains, a glycerol backbone, and a free or derivatized phosphate. Lysophospholipids only have a single fatty acyl chain (see figure 1).

SERUM

Fluid produced during blood coagulation. Many growth factors and mediators are released by platelets during clotting.

ECTO-ENZYME

An enzyme that is located on the outside of the cell. Primarily involved in metabolism of molecules in the interstitial space or bloodstream.

METALLOPROTEINASE

A class of metal-ion-requiring extracellular proteases.

G-PROTEIN-COUPLED RECEPTOR

A cell-surface receptor for small molecules, peptides and lipids that spans the plasma membrane seven times and signals via heterotrimeric G proteins.

NECROSIS

A form of cell death that is distinguished by autolysis.

ISCHAEMIA-REPERFUSION INJURY

Cellular injury that occurs when hypoxic tissue is reoxygenated. A significant problem in stroke, heart attacks and kidney injury.

MILDLY OXIDIZED LDL

Low-density lipoprotein (LDL) is present in plasma. It is a large spherical particle that is made up of cholesterol, cholesteryl esters, phospholipids and a single protein that organizes the particle. Under oxidative stress, LDLs become modified, resulting in alterations in lipid composition.

ATHEROSCLEROSIS

Narrowing of the blood vessels due to deposition of 'plaque' following injury. It is a frequent cause of cardiovascular disease, including heart attacks and stroke.

ADIPOGENESIS

Development of fat cells (adipocytes) and formation of lipid bodies in adipocytes.

PHOSPHOLIPASE

An enzyme that cleaves phospholipids.

SPHINGOSINE-1-PHOSPHATE

A small lipid that is similar to LPA, but with a sphingosine rather than a glycerol backbone.

PLASMA

Fluid that is present in blood in vivo.

ASCITES FLUID

Fluid that accumulates in the peritoneal cavity of ovarian cancer patients and occasionally in patients with other diseases, such as liver failure.

LPPS

(Lipid phosphate phosphohydrolases). Cleave phosphate from LPA, sphingosine-1-phosphate, ceramide-1-phosphate and phosphatidic acid.

GAS CHROMATOGRAPHY

A method that is used to separate and identify small molecules.

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Mills, G., Moolenaar, W. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer 3, 582–591 (2003). https://doi.org/10.1038/nrc1143

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