title: The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis.
abstract: OBJECTIVE
  Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and GPR55 agonist, L-α-lysophosphatidylinositol (LPI), into the circulation. We aimed to assess the involvement of this agonist and its receptor in ovarian cancer angiogenesis.
  
  
  METHODS
  Secretion of LPI by three ovarian cancer cell lines (OVCAR-3, OVCAR-5 and COV-362) was tested by mass spectrometry. Involvement of cancer cell-derived LPI on angiogenesis was tested in the in vivo chicken chorioallantoic membrane (CAM) assay along with the assessment of the effect of LPI on proliferation, network formation, and migration of neonatal and adult human endothelial colony-forming cells (ECFCs). Engagement of GPR55 was verified by using its pharmacological inhibitor CID16020046 and diminution of GPR55 expression by four different target-specific siRNAs. To study underlying signal transduction, Western blot analysis was performed.
  
  
  RESULTS
  Ovarian carcinoma cell-derived LPI stimulated angiogenesis in the CAM assay. Applied LPI stimulated proliferation, network formation, and migration of neonatal ECFCs in vitro and angiogenesis in the in vivo CAM. The pharmacological GPR55 inhibitor CID16020046 inhibited LPI-stimulated ECFC proliferation, network formation and migration in vitro as well as ovarian carcinoma cell- and LPI-induced angiogenesis in vivo. Four target-specific siRNAs against GPR55 prevented these effects of LPI on angiogenesis. These pro-angiogenic effects of LPI were transduced by GPR55-dependent phosphorylation of ERK1/2 and p38 kinase.
  
  
  CONCLUSIONS
  We conclude that inhibiting the pro-angiogenic LPI/GPR55 pathway appears a promising target against angiogenesis in ovarian carcinoma.
authors.affiliation: Institute for Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.|Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Hofmann
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: FAS Small Molecule Mass Spectrometry Facility, Harvard University, Boston, MA, USA.
authors.forename: Sunia A
authors.initials: SA
authors.lastname: Trauger
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Hironao
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Experimental and Clinical Cell Therapy Institute, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Strunk
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: Institute for Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000502:physiology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C524885:GPR55 protein, human; D008246:Lysophospholipids; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; C025449:lysophosphatidylinositol; D048051:p38 Mitogen-Activated Protein Kinases