Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches.

Détails

Ressource 1Télécharger: BIB_EC95917CF5CA.P001.pdf (5851.71 [Ko])
Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_EC95917CF5CA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches.
Périodique
PLoS Computational Biology
Auteur(s)
Guex N., Crespo I., Bron S., Ifticene-Treboux A., Faes-Van't Hull E., Kharoubi S., Liechti R., Werffeli P., Ibberson M., Majo F., Nicolas M., Laurent J., Garg A., Zaman K., Lehr H.A., Stevenson B.J., Rüegg C., Coukos G., Delaloye J.F., Xenarios I., Doucey M.A.
ISSN
1553-7358 (Electronic)
ISSN-L
1553-734X
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
11
Numéro
3
Pages
e1004050
Langue
anglais
Résumé
Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.
Pubmed
Web of science
Open Access
Oui
Création de la notice
01/05/2015 17:12
Dernière modification de la notice
20/08/2019 16:14
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