Loss of Pten promotes angiogenesis and enhanced vegfaa expression in zebrafish
- Authors
- Choorapoikayil, S., Weijts, B., Kers, R., de Bruin, A., and den Hertog, J.
- ID
- ZDB-PUB-130708-29
- Date
- 2013
- Source
- Disease models & mechanisms 6(5): 1159-66 (Journal)
- Registered Authors
- Choorapoikayil, Suma, den Hertog, Jeroen, Weijts, Bart
- Keywords
- none
- MeSH Terms
-
- Vascular Endothelial Growth Factor A/metabolism*
- Zebrafish/embryology
- Zebrafish/metabolism*
- Hemangiosarcoma/blood supply
- Hemangiosarcoma/drug therapy
- Hemangiosarcoma/pathology
- Haploinsufficiency/drug effects
- Haploinsufficiency/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Animals
- Chromones/pharmacology
- Chromones/therapeutic use
- Indoles/pharmacology
- Indoles/therapeutic use
- Mutation/genetics
- Drug Therapy, Combination
- Up-Regulation/drug effects
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism*
- Neovascularization, Pathologic/pathology*
- Humans
- Phosphoprotein Phosphatases/deficiency*
- Phosphoprotein Phosphatases/genetics
- Phosphoprotein Phosphatases/metabolism
- Pyrroles/pharmacology
- Pyrroles/therapeutic use
- Zebrafish Proteins/deficiency*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Morpholines/pharmacology
- Morpholines/therapeutic use
- Proto-Oncogene Proteins c-akt/metabolism
- Pseudopodia/drug effects
- Pseudopodia/metabolism
- PubMed
- 23720233 Full text @ Dis. Model. Mech.
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.
