Tumor cell migration, invasion, and angiogenesis are important determinants of tumor aggressiveness, and these traits have been associated with the motility-stimulating protein autotaxin (ATX). This protein is a member of the ectonucleotide pyrophosphatase and phosphodiesterase family of enzymes, but unlike other members of this family, ATX also possesses lysophospholipase D (LPLD) activity. This enzymatic activity hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and sphingosylphosphorylcholine to sphingosine-1-phosphate (S1P). The ATX products, LPA and S1P, are bioactive phospholipids associated with cell growth, motility, and survival, as well as with blood vessel formation and maturation. Previously, we published data supporting a potential positive feedback loop between VEGF, ATX expression, LPA, and VEGFR2 expression in ovarian cancer cell lines. Recently published work with human umbilical vein and human umbilical artery cells has shown that VEGF acting via VEGFR2 also stimulates ATX expression in endothelial cells. The resulting elevation in LPA levels modulates expression of Akt isomers, particularly Akt-2. In contrast, down-regulation of ATX secretion in human umbilical vein cells virtually abrogates cell motility responses to VEGF, LPA, ATX, and lysophosphatidylcholine and significantly reduced responses to S1P and sphingosylphosphorylcholine. We continue to elucidate the pathways that contribute to the ATX effect on ovarian cancer and endothelial cells. Although ATX appears to affect both tumor angiogenesis and embryonic vascular development, the mechanisms for these effects are poorly understood. Our data suggest that the ATX role in angiogenesis is closely linked to VEGF expression and activity as well as to Akt regulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010935-04
Application #
8349236
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$237,348
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Ptaszynska, Malgorzata M; Pendrak, Michael L; Stracke, Mary L et al. (2010) Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration. Mol Cancer Res 8:309-21
Im, Eunok; Motiejunaite, Ruta; Aranda, Jorge et al. (2010) Phospholipase Cgamma activation drives increased production of autotaxin in endothelial cells and lysophosphatidic acid-dependent regression. Mol Cell Biol 30:2401-10
Koh, Eunjin; Bandle, Russell W; Roberts, David D et al. (2009) Novel point mutations attenuate autotaxin activity. Lipids Health Dis 8:4