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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,
Pubmed
Bayliss,
Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish.
2006,
Pubmed
Berghmans,
Zebrafish based assays for the assessment of cardiac, visual and gut function--potential safety screens for early drug discovery.
2008,
Pubmed
Carmeliet,
Angiogenesis in health and disease.
2003,
Pubmed
Chang,
Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila.
2008,
Pubmed
Christensen,
Gene expression analysis defines the proximal tubule as the compartment for endocytic receptor-mediated uptake in the Xenopus pronephric kidney.
2008,
Pubmed
,
Xenbase
Cleaver,
VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus.
1998,
Pubmed
,
Xenbase
Cueni,
New insights into the molecular control of the lymphatic vascular system and its role in disease.
2006,
Pubmed
Dadras,
Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes.
2005,
Pubmed
Diamandis,
Chemical genetics reveals a complex functional ground state of neural stem cells.
2007,
Pubmed
Helbling,
The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis.
2000,
Pubmed
,
Xenbase
Hirakawa,
VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites.
2007,
Pubmed
Hirakawa,
Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells.
2003,
Pubmed
Hirakawa,
VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis.
2005,
Pubmed
Hong,
VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins.
2004,
Pubmed
Howland,
On the Effect of Removal of the Pronephros of the Amphibian Embryo.
1916,
Pubmed
Karkkainen,
Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins.
2004,
Pubmed
Kälin,
Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis.
2007,
Pubmed
,
Xenbase
Levine,
Fluorescent labeling of endothelial cells allows in vivo, continuous characterization of the vascular development of Xenopus laevis.
2003,
Pubmed
,
Xenbase
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
Mäkinen,
Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3.
2001,
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,
Chemical genetics: ligand-based discovery of gene function.
2000,
Pubmed
Tobler,
Tumor and lymph node lymphangiogenesis--impact on cancer metastasis.
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
