This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ren, J. Articles by Xu, Y. Search for Related Content PubMed PubMed Citation Articles by Ren, J. Articles by Xu, Y.

Lysophosphatidic Acid Is Constitutively Produced by Human Peritoneal Mesothelial Cells and Enhances Adhesion, Migration, and Invasion of Ovarian Cancer Cells

¹ Department of Cancer Biology, Lerner Research Institute and ² Department of Gynecology and Obstetrics, The Cleveland Clinic Foundation, Cleveland, Ohio; ³ Echelon Biosciences, Inc.; and ⁴ Department of Medicinal Chemistry, The University of Utah, Salt Lake City, Utah

Requests for reprints: Yan Xu, Department of Obstetrics and Gynecology, Indiana University, 975 W. Walnut St. IB355A, Indianapolis, IN 46202. Fax: 317-278-2884; E-mail: Xu2{at}iupui.edu.

Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal mesothelial cells constitutively produce LPA, which accounts for a significant portion of the chemotactic activity of the conditioned medium from peritoneal mesothelial cells to ovarian cancer cells. Both production of LPA by peritoneal mesothelial cells and the chemotactic activity in the conditioned medium can be blocked by HELSS [an inhibitor of the calcium-independent phospholipase A₂ (iPLA₂)] and AACOCF₃ [an inhibitor of both cytosolic PLA₂ (cPLA₂) and iPLA₂]. Moreover, cell-based enzymatic activity assays for PLA₂ indicate that peritoneal mesothelial cells have strong constitutive PLA₂ activity. Receptors for LPA, LPA₂, and LPA₃ are involved in the conditioned medium–induced chemotactic activity. Invasion of ovarian cancer cells into peritoneal mesothelial cells has also been analyzed and shown to require PLA₂, LPA receptors, and the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Thus, we show here, for the first time, that human peritoneal mesothelial cells constitutively produce bioactive lipid signaling molecules, such as LPA, via iPLA₂ and/or cPLA₂ activities. Conditioned medium from peritoneal mesothelial cells stimulate migration, adhesion, and invasion of ovarian cancer cells, and may play similar roles in vivo. (Cancer Res 2006; 66(6): 3006-14)

This article has been cited by other articles:

				H. Li, D. Wang, H. Zhang, K. Kirmani, Z. Zhao, R. Steinmetz, and Y. Xu Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice Mol. Cancer Ther., June 1, 2009; 8(6): 1692 - 1701. [Abstract] [Full Text] [PDF]

				M. Komachi, H. Tomura, E. Malchinkhuu, M. Tobo, C. Mogi, T. Yamada, T. Kimura, A. Kuwabara, H. Ohta, D.-S. Im, et al. LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites Carcinogenesis, March 1, 2009; 30(3): 457 - 465. [Abstract] [Full Text] [PDF]

				J. K. Slack-Davis, K. A. Atkins, C. Harrer, E. D. Hershey, and M. Conaway Vascular Cell Adhesion Molecule-1 Is a Regulator of Ovarian Cancer Peritoneal Metastasis Cancer Res., February 15, 2009; 69(4): 1469 - 1476. [Abstract] [Full Text] [PDF]

				A. Ambesi and P. J. McKeown-Longo Anastellin, the Angiostatic Fibronectin Peptide, Is a Selective Inhibitor of Lysophospholipid Signaling Mol. Cancer Res., February 1, 2009; 7(2): 255 - 265. [Abstract] [Full Text] [PDF]

				G. Ferry, N. Moulharat, J.-P. Pradere, P. Desos, A. Try, A. Genton, A. Giganti, M. Beucher-Gaudin, M. Lonchampt, M. Bertrand, et al. S32826, A Nanomolar Inhibitor of Autotaxin: Discovery, Synthesis and Applications as a Pharmacological Tool J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 809 - 819. [Abstract] [Full Text] [PDF]

				S. Yu, M. M. Murph, Y. Lu, S. Liu, H. S. Hall, J. Liu, C. Stephens, X. Fang, and G. B. Mills Lysophosphatidic Acid Receptors Determine Tumorigenicity and Aggressiveness of Ovarian Cancer Cells J Natl Cancer Inst, November 19, 2008; 100(22): 1630 - 1642. [Abstract] [Full Text] [PDF]

				D. Wang, Z. Zhao, A. Caperell-Grant, G. Yang, S. C. Mok, J. Liu, R. M. Bigsby, and Y. Xu S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells Mol. Cancer Ther., July 1, 2008; 7(7): 1993 - 2002. [Abstract] [Full Text] [PDF]

				M. M. Ptaszynska, M. L. Pendrak, R. W. Bandle, M. L. Stracke, and D. D. Roberts Positive Feedback between Vascular Endothelial Growth Factor-A and Autotaxin in Ovarian Cancer Cells Mol. Cancer Res., March 1, 2008; 6(3): 352 - 363. [Abstract] [Full Text] [PDF]

				N. Said, M. J. Socha, J. J. Olearczyk, A. A. Elmarakby, J. D. Imig, and K. Motamed Normalization of the Ovarian Cancer Microenvironment by SPARC Mol. Cancer Res., October 1, 2007; 5(10): 1015 - 1030. [Abstract] [Full Text] [PDF]

				Z. Zhao, Y. Xiao, P. Elson, H. Tan, S. J. Plummer, M. Berk, P. P. Aung, I. C. Lavery, J. P. Achkar, L. Li, et al. Plasma Lysophosphatidylcholine Levels: Potential Biomarkers for Colorectal Cancer J. Clin. Oncol., July 1, 2007; 25(19): 2696 - 2701. [Abstract] [Full Text] [PDF]

				X. Zhao, D. Wang, Z. Zhao, Y. Xiao, S. Sengupta, Y. Xiao, R. Zhang, K. Lauber, S. Wesselborg, L. Feng, et al. Caspase-3-dependent Activation of Calcium-independent Phospholipase A2 Enhances Cell Migration in Non-apoptotic Ovarian Cancer Cells J. Biol. Chem., September 29, 2006; 281(39): 29357 - 29368. [Abstract] [Full Text] [PDF]

				S. Tsuda, S. Okudaira, K. Moriya-Ito, C. Shimamoto, M. Tanaka, J. Aoki, H. Arai, K. Murakami-Murofushi, and T. Kobayashi Cyclic Phosphatidic Acid Is Produced by Autotaxin in Blood J. Biol. Chem., September 8, 2006; 281(36): 26081 - 26088. [Abstract] [Full Text] [PDF]

				K.-S. Kim, S. Sengupta, M. Berk, Y.-G. Kwak, P. F. Escobar, J. Belinson, S. C. Mok, and Y. Xu Hypoxia Enhances Lysophosphatidic Acid Responsiveness in Ovarian Cancer Cells and Lysophosphatidic Acid Induces Ovarian Tumor Metastasis In vivo Cancer Res., August 15, 2006; 66(16): 7983 - 7990. [Abstract] [Full Text] [PDF]