title: Loss of Pten promotes angiogenesis and enhanced vegfaa expression in zebrafish.
abstract: Angiogenesis, the emergence of vessels from an existing vascular network, is pathologically associated with tumor progression and is of great interest for therapeutic intervention. PTEN is a frequently mutated tumor suppressor and has been linked to the progression of many types of tumors, including hemangiosarcomas in zebrafish. Here, we report that mutant zebrafish embryos lacking functional Pten exhibit enhanced angiogenesis, accompanied by elevated levels of phosphorylated Akt (pAkt). Inhibition of phosphoinositide 3-kinase (PI3K) by LY294002 treatment and application of sunitinib, a widely used anti-angiogenic compound, suppressed enhanced angiogenesis in Pten mutants. Vegfaa has a crucial role in angiogenesis and vegfaa expression was upregulated in embryos lacking functional Pten. Interestingly, vegfaa expression was also upregulated in hemangiosarcomas from haploinsufficient adult zebrafish Pten mutants. Elevated vegfaa expression in mutant embryos lacking functional Pten was suppressed by LY294002. Surprisingly, sunitinib treatment dramatically enhanced vegfaa expression in Pten mutant embryos, which might account for tumor relapse in human patients who are treated with sunitinib. Combined treatment with suboptimal concentrations of sunitinib and LY294002 rescued enhanced angiogenesis in pten mutant embryos without the dramatic increase in vegfaa expression, suggesting a new approach for therapeutic intervention in VEGFR-signaling-dependent tumors.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center, Utrecht, The Netherlands.
authors.forename: Suma
authors.initials: S
authors.lastname: Choorapoikayil
authors.forename: Bart
authors.initials: B
authors.lastname: Weijts
authors.forename: Rianne
authors.initials: R
authors.lastname: Kers
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D057895:Haploinsufficiency / Q000187:drug effects / Q000235:genetics; D006394:Hemangiosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077210:Sunitinib; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: D002867:Chromones; D007211:Indoles; D009025:Morpholines; D011758:Pyrroles; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases; C511364:Ptena protein, zebrafish; C511365:Ptenb protein, zebrafish; D000077210:Sunitinib