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An in vivo chemical library screen in Xenopus tadpoles reveals novel pathways involved in angiogenesis and lymphangiogenesis.
Kälin RE, Bänziger-Tobler NE, Detmar M, Brändli AW.
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Angiogenesis and lymphangiogenesis are essential for organogenesis but also play important roles in tissue regeneration, chronic inflammation, and tumor progression. Here we applied in vivo forward chemical genetics to identify novel compounds and biologic mechanisms involved in (lymph)angiogenesis in Xenopus tadpoles. A novel 2-step screening strategy involving a simple phenotypic read-out (edema formation or larval lethality) followed by semiautomated in situ hybridization was devised and used to screen an annotated chemical library of 1280 bioactive compounds. We identified 32 active compounds interfering with blood vascular and/or lymphatic development in Xenopus. Selected compounds were also tested for activities in a variety of endothelial in vitro assays. Finally, in a proof-of-principle study, the adenosine A1 receptor antagonist 7-chloro-4-hydroxy-2-phenyl-1,8-naphthyridine, an inhibitor of blood vascular and lymphatic development in Xenopus, was shown to act also as a potent antagonist of VEGFA-induced adult neovascularization in mice. Taken together, the present chemical library screening strategy in Xenopus tadpoles represents a rapid and highly efficient approach to identify novel pathways involved in (lymph)angiogenesis. In addition, the recovered compounds represent a rich resource for in-depth analysis, and their drug-like features will facilitate further evaluation in preclinical models of inflammation and cancer metastasis.
Alitalo,
Lymphangiogenesis in development and human disease.
2005, Pubmed
Alitalo,
Lymphangiogenesis in development and human disease.
2005,
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2006,
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2003,
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2008,
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Pubmed
,
Xenbase Cleaver,
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1998,
Pubmed
,
Xenbase Cueni,
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2006,
Pubmed Dadras,
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2005,
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2007,
Pubmed Helbling,
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2000,
Pubmed
,
Xenbase Hirakawa,
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2005,
Pubmed Hirakawa,
VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites.
2007,
Pubmed Hirakawa,
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2003,
Pubmed Hong,
VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins.
2004,
Pubmed Howland,
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1916,
Pubmed Kälin,
Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis.
2007,
Pubmed
,
Xenbase Karkkainen,
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2004,
Pubmed Levine,
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2003,
Pubmed
,
Xenbase Mäkinen,
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2001,
Pubmed Mandriota,
Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis.
2001,
Pubmed Milan,
Drugs that induce repolarization abnormalities cause bradycardia in zebrafish.
2003,
Pubmed Min,
Forward chemical genetic approach identifies new role for GAPDH in insulin signaling.
2007,
Pubmed Ny,
A genetic Xenopus laevis tadpole model to study lymphangiogenesis.
2005,
Pubmed
,
Xenbase Parng,
Zebrafish: a preclinical model for drug screening.
2002,
Pubmed Pepper,
Lymphangiogenesis and tumor metastasis.
2003,
Pubmed Peterson,
Discovery and use of small molecules for probing biological processes in zebrafish.
2004,
Pubmed Petrova,
Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor.
2002,
Pubmed Pyriochou,
Soluble guanylyl cyclase activation promotes angiogenesis.
2006,
Pubmed Raciti,
Organization of the pronephric kidney revealed by large-scale gene expression mapping.
2008,
Pubmed
,
Xenbase Ram,
Hypertension, possible vascular protection and lercanidipine.
2006,
Pubmed Rickardson,
Screening of an annotated compound library for drug activity in a resistant myeloma cell line.
2006,
Pubmed Roesli,
Identification of the surface-accessible, lineage-specific vascular proteome by two-dimensional peptide mapping.
2008,
Pubmed Root,
Biological mechanism profiling using an annotated compound library.
2003,
Pubmed Sachidanandan,
Identification of a novel retinoid by small molecule screening with zebrafish embryos.
2008,
Pubmed Seiffert,
Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors.
2000,
Pubmed Serbedzija,
Zebrafish angiogenesis: a new model for drug screening.
1999,
Pubmed Skobe,
Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.
2001,
Pubmed Stacker,
VEGF-D promotes the metastatic spread of tumor cells via the lymphatics.
2001,
Pubmed Stockwell,
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2000,
Pubmed Tobler,
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2006,
Pubmed Tomlinson,
Xenopus as a model organism in developmental chemical genetic screens.
2005,
Pubmed
,
Xenbase Tran,
Automated, quantitative screening assay for antiangiogenic compounds using transgenic zebrafish.
2007,
Pubmed Zon,
In vivo drug discovery in the zebrafish.
2005,
Pubmed
