[en] 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.
Methodology/Principal Findings: 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/Significance: 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Nguyen, Ngoc-Quynh-Nhu ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Castermans, Karolien
Berndt, Sarah
Herkenne, Stéphanie ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Tabruyn, Sébastien ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Blacher, Silvia ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Lion, Michelle ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Martial, Joseph ; Université de Liège - ULiège > Département des sciences de la vie > Département des sciences de la vie
Struman, Ingrid ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Language :
English
Title :
The Antiangiogenic 16K Prolactin Impairs Functional Tumor Neovascularization by Inhibiting Vessel Maturation
Publication date :
07 November 2011
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, San Franscisco, United States - California
FP7 - 201279 - MICROENVIMET - Understanding and fighting metastasis by modulating the tumour microenvironment through interference with the protease network.
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