Ovarian Cancer pp 269-296 | Cite as

Lysophosphatidic Acid and Invasion

  • Fengqiang WangEmail author
  • David A. Fishman
Part of the Cancer Treatment and Research book series (CTAR, volume 149)


Lysophosphatidic acid (LPA) is a small, bioactive phospholipid produced by activated platelets, mesothelial cells, macrophage, endothelial cells, fibroblasts, adipocytes, and some cancer cells. It is involved in multiple cellular events of almost every mammalian cell type. Upon binding to G-protein–coupled receptors (GPCRs), LPA exerts a myriad of biological effects, including cell proliferation/survival, induction of neurite retraction, inhibition of gap junctional communication, and cell motility. The estimated concentrations of active, albumin-bound LPA in serum are in the range 1–5 µmol/L. Physiologic and pathophysiologic responses to LPA include wound healing, production of angiogenic factors, chemotaxis, neointima formation, tumor cell invasion, metastasis, and cell cycle progression. A large body of evidence suggests that LPA is relevant to the pathogenesis of epithelial ovarian cancer (EOC). LPA is elevated in the blood and ascites of women with ovarian cancer with...


Vascular Endothelial Growth Factor Epithelial Ovarian Cancer Ovarian Cancer Cell Vascular Endothelial Growth Factor Expression SKOV3 Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Lee J, Park SY, Lee EK, et al. Activation of hypoxia-inducible factor-1alpha is necessary for lysophosphatidic acid-induced vascular endothelial growth factor expression. Clin Cancer Res. Nov 1 2006;12(21):6351–6358.CrossRefPubMedGoogle Scholar
  2. 2.
    Park SY, Jeong KJ, Lee J, et al. Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol. Cancer Lett. Dec 8 2007;258(1):63–69.CrossRefPubMedGoogle Scholar
  3. 3.
    Said NA, Najwer I, Socha MJ, Fulton DJ, Mok SC, Motamed K. SPARC inhibits LPA-mediated mesothelial-ovarian cancer cell crosstalk. Neoplasia. Jan 2007;9(1):23–35.CrossRefPubMedGoogle Scholar
  4. 4.
    Xu Y, Shen Z, Wiper DW, et al. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA. Aug 26 1998;280(8):719–723.CrossRefPubMedGoogle Scholar
  5. 5.
    Baker DL, Morrison P, Miller B, et al. Plasma lysophosphatidic acid concentration and ovarian cancer. JAMA. Jun 19 2002;287(23):3081–3082.CrossRefPubMedGoogle Scholar
  6. 6.
    Sutphen R, Xu Y, Wilbanks GD, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev. Jul 2004;13(7):1185–1191.PubMedGoogle Scholar
  7. 7.
    Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer. Aug 2003;3(8):582–591.CrossRefPubMedGoogle Scholar
  8. 8.
    Murph M, Tanaka T, Liu S, Mills GB. Of spiders and crabs: the emergence of lysophospholipids and their metabolic pathways as targets for therapy in cancer. Clin Cancer Res. Nov 15 2006;12(22):6598–6602.CrossRefPubMedGoogle Scholar
  9. 9.
    Sengupta S, Kim KS, Berk MP, et al. Lysophosphatidic acid downregulates tissue inhibitor of metalloproteinases, which are negatively involved in lysophosphatidic acid-induced cell invasion. Oncogene. May 3 2007;26(20):2894–2901.CrossRefPubMedGoogle Scholar
  10. 10.
    Ren J, Xiao YJ, Singh LS, et al. Lysophosphatidic acid is constitutively produced by human peritoneal mesothelial cells and enhances adhesion, migration, and invasion of ovarian cancer cells. Cancer Res. Mar 15 2006;66(6):3006–3014.CrossRefPubMedGoogle Scholar
  11. 11.
    Kim KS, Sengupta S, Berk M, et al. Hypoxia enhances lysophosphatidic acid responsiveness in ovarian cancer cells and lysophosphatidic acid induces ovarian tumor metastasis in vivo. Cancer Res. Aug 15 2006;66(16):7983–7990.CrossRefPubMedGoogle Scholar
  12. 12.
    Ptaszynska MM, Pendrak ML, Bandle RW, Stracke ML, Roberts DD. Positive Feedback between Vascular Endothelial Growth Factor-A and Autotaxin in Ovarian Cancer Cells. Mol Cancer Res. Mar 2008;6(3):352–363.CrossRefPubMedGoogle Scholar
  13. 13.
    Tanyi JL, Morris AJ, Wolf JK, et al. The human lipid phosphate phosphatase-3 decreases the growth, survival, and tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid signaling cascade as a target for therapy in ovarian cancer. Cancer Res. Mar 1 2003;63(5):1073–1082.PubMedGoogle Scholar
  14. 14.
    Tanyi JL, Hasegawa Y, Lapushin R, et al. Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer. Clin Cancer Res. Sep 1 2003;9(10 Pt 1):3534–3545.PubMedGoogle Scholar
  15. 15.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. Feb 1997;18(1):4–25.CrossRefPubMedGoogle Scholar
  16. 16.
    Hu YL, Tee MK, Goetzl EJ, et al. Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. J Natl Cancer Inst. May 16 2001;93(10):762–768.CrossRefPubMedGoogle Scholar
  17. 17.
    So J, Wang FQ, Navari J, Schreher J, Fishman DA. LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2). Gynecol Oncol. Jun 2005;97(3):870–878.PubMedGoogle Scholar
  18. 18.
    Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. Oct 1989;84(4):1045–1049.CrossRefPubMedGoogle Scholar
  19. 19.
    Ivarsson K, Runesson E, Sundfeldt K, et al. The chemotactic cytokine interleukin-8–a cyst fluid marker for malignant epithelial ovarian cancer? Gynecol Oncol. Dec 1998;71(3):420–423.CrossRefPubMedGoogle Scholar
  20. 20.
    Schwartz BM, Hong G, Morrison BH, et al. Lysophospholipids increase interleukin-8 expression in ovarian cancer cells. Gynecol Oncol. May 2001;81(2):291–300.CrossRefPubMedGoogle Scholar
  21. 21.
    Fang X, Yu S, Bast RC, et al. Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J Biol Chem. Mar 5 2004;279(10):9653–9661.CrossRefPubMedGoogle Scholar
  22. 22.
    So J, Navari J, Wang FQ, Fishman DA. Lysophosphatidic acid enhances epithelial ovarian carcinoma invasion through the increased expression of interleukin-8. Gynecol Oncol. Nov 2004;95(2):314–322.CrossRefPubMedGoogle Scholar
  23. 23.
    Li H, Ye X, Mahanivong C, Bian D, Chun J, Huang S. Signaling mechanisms responsible for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. J Biol Chem. Mar 18 2005;280(11):10564–10571.CrossRefPubMedGoogle Scholar
  24. 24.
    Schmalfeldt B, Prechtel D, Harting K, et al. Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer. Clin Cancer Res. Aug 2001;7(8):2396–2404.PubMedGoogle Scholar
  25. 25.
    Murthi P, Barker G, Nowell CJ, et al. Plasminogen fragmentation and increased production of extracellular matrix-degrading proteinases are associated with serous epithelial ovarian cancer progression. Gynecol Oncol. Jan 2004;92(1):80–88.CrossRefPubMedGoogle Scholar
  26. 26.
    Fishman DA, Kearns A, Larsh S, Enghild JJ, Stack MS. Autocrine regulation of growth stimulation in human epithelial ovarian carcinoma by serine-proteinase-catalysed release of the urinary-type-plasminogen-activator N-terminal fragment. Biochem J. Aug 1 1999;341 ( Pt 3):765–769.CrossRefPubMedGoogle Scholar
  27. 27.
    Kobayashi H, Suzuki M, Tanaka Y, Hirashima Y, Terao T. Suppression of urokinase expression and invasiveness by urinary trypsin inhibitor is mediated through inhibition of protein kinase C- and MEK/ERK/c-Jun-dependent signaling pathways. J Biol Chem. Jan 19 2001;276(3):2015–2022.CrossRefPubMedGoogle Scholar
  28. 28.
    Sato S, Kopitz C, Schmalix WA, et al. High-affinity urokinase-derived cyclic peptides inhibiting urokinase/urokinase receptor-interaction: effects on tumor growth and spread. FEBS Lett. Sep 25 2002;528(1–3):212–216.CrossRefPubMedGoogle Scholar
  29. 29.
    Suzuki M, Kobayashi H, Tanaka Y, et al. Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin. Int J Cancer. Apr 10 2003;104(3):289–302.CrossRefPubMedGoogle Scholar
  30. 30.
    Pustilnik TB, Estrella V, Wiener JR, et al. Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clin Cancer Res. Nov 1999;5(11):3704-3710.PubMedGoogle Scholar
  31. 31.
    Huang MC, Lee HY, Yeh CC, Kong Y, Zaloudek CJ, Goetzl EJ. Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2). Oncogene. Jan 8 2004;23(1):122–129.CrossRefPubMedGoogle Scholar
  32. 32.
    Mahanivong C, Chen HM, Yee SW, Pan ZK, Dong Z, Huang S. Protein kinase C alpha-CARMA3 signaling axis links Ras to NF-kappa B for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. Oncogene. Feb 21 2008;27(9):1273–1280.CrossRefPubMedGoogle Scholar
  33. 33.
    Estrella VC, Eder AM, Liu S, et al. Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway. Int J Oncol. Aug 2007;31(2):441–449.PubMedGoogle Scholar
  34. 34.
    Gil OD, Lee C, Ariztia EV, et al. Lysophosphatidic acid (LPA) promotes E-cadherin ectodomain shedding and OVCA429 cell invasion in an uPA-dependent manner. Gynecol Oncol. Feb 2008;108(2):361–369.CrossRefPubMedGoogle Scholar
  35. 35.
    Overall CM, Lopez-Otin C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer. Sep 2002;2(9):657–672.CrossRefPubMedGoogle Scholar
  36. 36.
    Ellerbroek SM, Fishman DA, Kearns AS, Bafetti LM, Stack MS. Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin. Cancer Res. Apr 1 1999;59(7):1635–1641.PubMedGoogle Scholar
  37. 37.
    Davidson B, Goldberg I, Gotlieb WH, et al. High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin Exp Metastasis. 1999;17(10):799–808.CrossRefPubMedGoogle Scholar
  38. 38.
    Huang S, Van Arsdall M, Tedjarati S, et al. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst. Aug 7 2002;94(15):1134–1142.PubMedGoogle Scholar
  39. 39.
    Butler GS, Butler MJ, Atkinson SJ, et al. The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem. Jan 9 1998;273(2):871–880.CrossRefPubMedGoogle Scholar
  40. 40.
    Fishman DA, Bafetti LM, Stack MS. Membrane-type matrix metalloproteinase expression and matrix metalloproteinase-2 activation in primary human ovarian epithelial carcinoma cells. Invasion Metastasis. 1996;16(3):150–159.PubMedGoogle Scholar
  41. 41.
    Fishman DA, Liu Y, Ellerbroek SM, Stack MS. Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells. Cancer Res. Apr 1 2001;61(7):3194–3199.PubMedGoogle Scholar
  42. 42.
    Symowicz J, Adley BP, Woo MM, Auersperg N, Hudson LG, Stack MS. Cyclooxygenase-2 functions as a downstream mediator of lysophosphatidic acid to promote aggressive behavior in ovarian carcinoma cells. Cancer Res. Mar 15 2005;65(6):2234–2242.CrossRefPubMedGoogle Scholar
  43. 43.
    Do TV, Symowicz JC, Berman DM, et al. Lysophosphatidic acid down-regulates stress fibers and up-regulates pro-matrix metalloproteinase-2 activation in ovarian cancer cells. Mol Cancer Res. Feb 2007;5(2):121–131.CrossRefPubMedGoogle Scholar
  44. 44.
    Wang FQ, Smicun Y, Calluzzo N, Fishman DA. Inhibition of matrilysin expression by antisense or RNA interference decreases lysophosphatidic acid-induced epithelial ovarian cancer invasion. Mol Cancer Res. Nov 2006;4(11):831–841.CrossRefPubMedGoogle Scholar
  45. 45.
    Gschwind A, Hart S, Fischer OM, Ullrich A. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. May 15 2003;22(10):2411–2421.CrossRefPubMedGoogle Scholar
  46. 46.
    Cao Y, Prescott SM. Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol. Mar 2002;190(3):279–286.CrossRefPubMedGoogle Scholar
  47. 47.
    Butler TA, Zhu C, Mueller RA, Fuller GC, Lemaire WJ, Woessner JF, Jr. Inhibition of ovulation in the perfused rat ovary by the synthetic collagenase inhibitor SC 44463. Biol Reprod. Jun 1991;44(6):1183–1188.CrossRefPubMedGoogle Scholar
  48. 48.
    Klimp AH, Hollema H, Kempinga C, van der Zee AG, de Vries EG, Daemen T. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in human ovarian tumors and tumor-associated macrophages. Cancer Res. Oct 1 2001;61(19):7305–7309.PubMedGoogle Scholar
  49. 49.
    Ershov AV, Bazan NG. Induction of cyclooxygenase-2 gene expression in retinal pigment epithelium cells by photoreceptor rod outer segment phagocytosis and growth factors. J Neurosci Res. Oct 15 1999;58(2):254–261.CrossRefPubMedGoogle Scholar
  50. 50.
    Harris AL. Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer. Jan 2002;2(1):38–47.CrossRefPubMedGoogle Scholar
  51. 51.
    Quintero M, Mackenzie N, Brennan PA. Hypoxia-inducible factor 1 (HIF-1) in cancer. Eur J Surg Oncol. Jun 2004;30(5):465–468.CrossRefPubMedGoogle Scholar
  52. 52.
    Lee CW, Rivera R, Gardell S, Dubin AE, Chun J. PR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J Biol Chem. Aug 18 2006;281(33):23589–23597.CrossRefPubMedGoogle Scholar
  53. 53.
    Shano S, Hatanaka K, Ninose S, Moriyama R, Tsujiuchi T, Fukushima N. A lysophosphatidic acid receptor lacking the PDZ-binding domain is constitutively active and stimulates cell proliferation. Biochim Biophys Acta. Dec 5 2007.Google Scholar
  54. 54.
    Hurst JH, Henkel PA, Brown AL, Hooks SB. Endogenous RGS proteins attenuate Galpha(i)-mediated lysophosphatidic acid signaling pathways in ovarian cancer cells. Cell Signal. Feb 2008;20(2):381–389.CrossRefPubMedGoogle Scholar
  55. 55.
    Lee MJ, Jeon ES, Lee JS, et al. Lysophosphatidic acid in malignant ascites stimulates migration of human mesenchymal stem cells. J Cell Biochem. Nov 20 2007.Google Scholar
  56. 56.
    Mukai M, Imamura F, Ayaki M, et al. Inhibition of tumor invasion and metastasis by a novel lysophosphatidic acid (cyclic LPA). Int J Cancer. Jun 11 1999;81(6):918–922.CrossRefPubMedGoogle Scholar
  57. 57.
    Goetzl EJ, Dolezalova H, Kong Y, et al. Distinctive expression and functions of the type 4 endothelial differentiation gene-encoded G protein-coupled receptor for lysophosphatidic acid in ovarian cancer. Cancer Res. Oct 15 1999;59(20):5370–5375.PubMedGoogle Scholar
  58. 58.
    Van Leeuwen FN, Olivo C, Grivell S, Giepmans BN, Collard JG, Moolenaar WH. Rac activation by lysophosphatidic acid LPA1 receptors through the guanine nucleotide exchange factor Tiam1. J Biol Chem. Jan 3 2003;278(1):400–406.CrossRefPubMedGoogle Scholar
  59. 59.
    Sawada K, Morishige K, Tahara M, et al. Lysophosphatidic acid induces focal adhesion assembly through Rho/Rho-associated kinase pathway in human ovarian cancer cells. Gynecol Oncol. Dec 2002;87(3):252–259.CrossRefPubMedGoogle Scholar
  60. 60.
    Bian D, Su S, Mahanivong C, et al. Lysophosphatidic Acid Stimulates Ovarian Cancer Cell Migration via a Ras-MEK Kinase 1 Pathway. Cancer Res. Jun 15 2004;64(12):4209–4217.CrossRefPubMedGoogle Scholar
  61. 61.
    Hashimoto K, Morishige K, Sawada K, et al. Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro. Cancer. Apr 1 2005;103(7):1529–1536.CrossRefPubMedGoogle Scholar
  62. 62.
    Sawada K, Morishige K, Tahara M, et al. Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho. Cancer Res. Nov 1 2002;62(21):6015–6020.PubMedGoogle Scholar
  63. 63.
    Smicun Y, Reierstad S, Wang FQ, Lee C, Fishman DA. S1P regulation of ovarian carcinoma invasiveness. Gynecol Oncol. Dec 2006;103(3):952–959.CrossRefPubMedGoogle Scholar
  64. 64.
    Smicun Y, Gil O, Devine K, Fishman DA. S1P and LPA have an attachment-dependent regulatory effect on invasion of epithelial ovarian cancer cells. Gynecol Oncol. Nov 2007;107(2):298–309.CrossRefPubMedGoogle Scholar
  65. 65.
    Park KS, Lee HY, Lee SY, et al. Lysophosphatidylethanolamine stimulates chemotactic migration and cellular invasion in SK-OV3 human ovarian cancer cells: involvement of pertussis toxin-sensitive G-protein coupled receptor. FEBS Lett. Sep 18 2007;581(23):4411–4416.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Obstetrics Gynecology, and Reproductive Sciences, Mount Sinai School of MedicineNew York UniversityNew YorkUSA

Personalised recommendations