title: The antiangiogenic 16K prolactin impairs functional tumor neovascularization by inhibiting vessel maturation.
abstract: BACKGROUND
  Angiogenesis, the formation of new blood vessels from existing vasculature, plays an essential role in tumor growth, invasion, and metastasis. 16K hPRL, the antiangiogenic 16-kDa N-terminal fragment of human prolactin was shown to prevent tumor growth and metastasis by modifying tumor vessel morphology.
  
  
  RESULTS
  Here we investigated the effect of 16K hPRL on tumor vessel maturation and on the related signaling pathways. We show that 16K hPRL treatment leads, in a murine B16-F10 tumor model, to a dysfunctional tumor vasculature with reduced pericyte coverage, and disruption of the PDGF-B/PDGFR-B, Ang/Tie2, and Delta/Notch pathways. In an aortic ring assay, 16K hPRL impairs endothelial cell and pericyte outgrowth from the vascular ring. In addition, 16K hPRL prevents pericyte migration to endothelial cells. This event was independent of a direct inhibitory effect of 16K hPRL on pericyte viability, proliferation, or migration. In endothelial cell-pericyte cocultures, we found 16K hPRL to disturb Notch signaling.
  
  
  CONCLUSIONS
  Taken together, our data show that 16K hPRL impairs functional tumor neovascularization by inhibiting vessel maturation and for the first time that an endogenous antiangiogenic agent disturbs Notch signaling. These findings provide new insights into the mechanisms of 16K hPRL action and highlight its potential for use in anticancer therapy.
authors.affiliation: Unit of Molecular Biology and Genetic Engineering, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: Ngoc-Quynh-Nhu
authors.initials: NQ
authors.lastname: Nguyen
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.forename: Sarah
authors.initials: S
authors.lastname: Berndt
authors.forename: Stephanie
authors.initials: S
authors.lastname: Herkenne
authors.forename: Sebastien P
authors.initials: SP
authors.lastname: Tabruyn
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Michelle
authors.initials: M
authors.lastname: Lion
authors.forename: Agnes
authors.initials: A
authors.lastname: Noel
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Martial
authors.forename: Ingrid
authors.initials: I
authors.lastname: Struman
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D018920:Coculture Techniques; D042783:Endothelial Cells; D051379:Mice; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D020286:Pericytes; D011388:Prolactin / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D011388:Prolactin
references.citation: Cancer Res. 2011 Sep 15;71(18):6073-83
references.pmid: 21803743
references.citation: Clin Cancer Res. 2006 Aug 15;12(16):4836-44
references.pmid: 16914569
references.citation: Cancer Res. 2006 Sep 1;66(17):8501-10
references.pmid: 16951162
references.citation: Blood. 2009 Aug 20;114(8):1707-16
references.pmid: 19411631
references.citation: Cancer Res. 2003 Jan 15;63(2):386-93
references.pmid: 12543792
references.citation: FASEB J. 2006 Dec;20(14):2630-2
references.pmid: 17065221
references.citation: Cancer Res. 2004 Apr 15;64(8):2725-33
references.pmid: 15087386
references.citation: Endocrinology. 1992 Mar;130(3):1380-6
references.pmid: 1311239
references.citation: Cancer Res. 2004 Mar 1;64(5):1675-86
references.pmid: 14996727
references.citation: Curr Opin Genet Dev. 2011 Feb;21(1):73-9
references.pmid: 21106363
references.citation: Blood. 2002 Nov 1;100(9):3361-8
references.pmid: 12384438
references.citation: Clin Cancer Res. 2007 Jun 1;13(11):3395-402
references.pmid: 17545548
references.citation: Mol Endocrinol. 2007 Jun;21(6):1422-9
references.pmid: 17405903
references.citation: Trends Mol Med. 2007 Sep;13(9):389-95
references.pmid: 17822956
references.citation: Microvasc Res. 2008 Mar;75(2):144-54
references.pmid: 17692341
references.citation: Mol Endocrinol. 1999 May;13(5):692-704
references.pmid: 10319320
references.citation: Mol Endocrinol. 2005 Jul;19(7):1932-42
references.pmid: 15746189
references.citation: Nat Rev Cancer. 2008 Aug;8(8):592-603
references.pmid: 18650835
references.citation: PLoS One. 2011 Apr 04;6(4):e18323
references.pmid: 21483741
references.citation: Cancer Res. 2007 Nov 15;67(22):11045-53
references.pmid: 18006851
references.citation: Cancer Res. 2007 Aug 1;67(15):7358-67
references.pmid: 17671206
references.citation: Blood. 2009 Apr 9;113(15):3631-9
references.pmid: 19218547
references.citation: Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2413-9
references.pmid: 15223825
references.citation: Cancer Res. 2001 Oct 1;61(19):7356-62
references.pmid: 11585777
references.citation: J Clin Invest. 1973 Nov;52(11):2745-56
references.pmid: 4355998
references.citation: Angiogenesis. 2001;4(2):133-42
references.pmid: 11806245
references.citation: Cancer Res. 2004 May 15;64(10):3586-92
references.pmid: 15150116
references.citation: Circ Res. 2009 Feb 27;104(4):466-75
references.pmid: 19150886
references.citation: Blood. 2007 Jun 1;109(11):4753-60
references.pmid: 17311993
references.citation: Lab Invest. 2008 Jan;88(1):11-7
references.pmid: 18059366
references.citation: Cancer Res. 2010 Mar 15;70(6):2213-23
references.pmid: 20197469
references.citation: Angiogenesis. 2009;12(2):125-37
references.pmid: 19449109
references.citation: Mol Ther. 2007 Dec;15(12):2094-100
references.pmid: 17726458
references.citation: J Exp Med. 2010 Mar 15;207(3):491-503
references.pmid: 20194633
references.citation: Nature. 2006 Dec 21;444(7122):1032-7
references.pmid: 17183313
references.citation: Eur J Cancer. 2010 May;46(8):1323-32
references.pmid: 20236818
references.citation: J Angiogenes Res. 2009 Nov 16;1:8
references.pmid: 20016694
references.citation: J Clin Invest. 2003 Oct;112(8):1142-51
references.pmid: 14561699
references.citation: Angiogenesis. 2008;11(1):41-51
references.pmid: 18256896
references.citation: Circ Res. 2005 Sep 16;97(6):512-23
references.pmid: 16166562
references.citation: Cancer Res. 2005 Oct 1;65(19):8690-7
references.pmid: 16204037
references.citation: Cell. 2009 Jun 12;137(6):1124-35
references.pmid: 19524514
references.citation: Cancer Res. 2007 Dec 1;67(23):11244-53
references.pmid: 18056450
references.citation: Arterioscler Thromb Vasc Biol. 2009 May;29(5):630-8
references.pmid: 19164813
references.citation: Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6374-8
references.pmid: 7541539
references.citation: Cell. 2006 Jan 13;124(1):161-73
references.pmid: 16413489
references.citation: Biol Proced Online. 2002 Oct 28;4:24-31
references.pmid: 12734572
references.citation: Cell. 2007 Feb 9;128(3):589-600
references.pmid: 17289576
references.citation: Genes Dev. 2004 Nov 15;18(22):2730-5
references.pmid: 15545631
references.citation: Mol Endocrinol. 2003 Sep;17(9):1815-23
references.pmid: 12791771
references.citation: Cancer Lett. 2009 Nov 1;284(2):222-8
references.pmid: 19473755
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: J Cell Sci. 2005 Aug 15;118(Pt 16):3759-68
references.pmid: 16105884
references.citation: Mol Cancer Ther. 2008 Dec;7(12):3670-84
references.pmid: 19074844
references.citation: Mol Endocrinol. 2000 Oct;14(10):1536-49
references.pmid: 11043570
references.citation: Nat Med. 2003 Jun;9(6):685-93
references.pmid: 12778167