Les études cliniques et les études in vitro confirment l’importance des galectines-1 et -3 dans l’angiogenèse.
Nous avons démontré que l’expression endothéliale de galectine-3 et l’hyperplasie endothéliocapillaire sont des facteurs de mauvais pronostic chez les patients immunocompétents atteints de lymphome primitif du système nerveux central.
Ces données doivent être validées au sein d’une plus large série de lymphomes primitifs du système nerveux central. Il faudrait également évaluer le potentiel de l’expression endothéliale de galectine-3 comme biomarqueur théranostique prédictif d’une réponse à un traitement anti-angiogénique dans une étude clinique.
Ce travail identifie également les VEGFRs comme biomarqueurs des cellules endothéliales dans un contexte tumoral, celles-ci étant caractérisées par une augmentation d’expression de VEGFR1 et une diminution d’expression de VEGFR2 en comparaison aux cellules endothéliales normales.
Ces résultats soulignent la nécessité de mieux caractériser, à partir de tissus humains, les cellules endothéliales dans un contexte tumoral et les cellules endothéliales quiescentes. Ceci permettrait de proposer de nouvelles cibles thérapeutiques spécifiques de l’angiogenèse tumorale.
Nous avons également mis en évidence la nécessité d’étudier l’angiogenèse in vitro à partir de lignées différentes de cellules endothéliales. Nos résultats nous permettent de proposer la lignée EA.hy926 comme modèle in vitro de cellules endothéliales dans un contexte tumoral. Il serait intéressant de caractériser plus précisément ce modèle (cellules EA.hy926), par exemple, à partir d’études de perméabilité, de coculture ou de modèles animaux. Afin de mieux appréhender l’hétérogénéité des cellules endothéliales, nous pourrions également comparer cette lignée avec des cellules endothéliales isolées à partir de différentes tumeurs humaines.
Nous démontrons que les galectines-1 et -3 sont des molécules antigéniques. Cependant, les voies de signalisation activées par les galectines semblent être les mêmes que celles du VEGF via l’activation du VEGFR2 dans nos modèles de cellules endothéliales normales et de cellules endothéliales dans un contexte tumoral. Alors que le rôle du VEGFR1 est encore controversé, nos données démontrent que la stimulation de l’angiogenèse tumorale par la combinaison des galectines-1 et -3 est liée à l’activation de ce recepteur. Nos résultats, intégrés aux données de la littérature, nous ont permis de poser l’hypothèse que la réponse endothéliale aux galectines-1 et -3 varie selon le microenvironnement (Figure 52). Dans un environnement normal, les galectines-1 et -3 extracellulaires stimulent l’angiogenèse via l’activation du VEGFR2 avec un effet additif lorsque les deux galectines sont présentes. Dans un environnement tumoral, chacune de ces galectines stimule l’angiogenèse via l’activation du VEGFR2 alors que la combinaison des deux galectines crée un effet synergique sur l’angiogenèse via l’activation du VEGFR1.
Ces résultats ouvrent de nouvelles perspectives de recherche sur les interactions entre la galectine-1 et -3 ainsi que sur les mécanismes d’action de ces galectines sur les VEGFRs. Parmi les pistes potentielles, nous favorisons l’hypothèse que les galectines, par la formation d’un treillis à la surface cellulaire, pourraient moduler l’endocytose des VEGFRs. Cette inhibition de l’endocytose des VEGFRs par les galectines permettrait une amplification du signal transmis par ces récepteurs.
Ce travail souligne que les galectines-1 et -3 représentent une cible thérapeutique intéressante en terme de thérapie anti-angiogénique. Toutefois, comme l’expression endothéliale des galectines-1 et -3 est différente selon la localisation tumorale, il faudra tenir compte de l’hétérogénéité des cellules endothéliales pour évaluer l’efficacité d’un traitement anti-angiogénique ciblant la galectine-1 ou la galectine-3. De plus, l’effet synergique des galectines-1 et -3 observé in vitro pour l’angiogenèse tumorale doit faire envisager une thérapie couplée ciblant ces deux galectines. La combinaison de ces thérapies avec des inhibiteurs des VEGFRs devra également être évaluée.
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