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

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 HA, Stevenson BJ, Rüegg C, Coukos G, Delaloye JF, Xenarios I, Doucey MA - PLoS Comput. Biol. (2015)

Bottom Line: Angiogenesis plays a key role in tumor growth and cancer progression.In silico predicted perturbations were validated experimentally using 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.

View Article: PubMed Central - PubMed

Affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.

ABSTRACT
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.

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Experimental validation of in silico predicted treatments using ivdTEM.TEM differentiated in vitro were exposed to the treatments predicted in silico and their changes in TIE-2 and VEGFR-1 expression (A) and pro-angiogenic activity (B) measured by flow cytometry and in vitro angiogenesis sprouting assay respectively. The impact of inhibitory treatments was examined on ivdTEM previously treated with TNF-α/PlGF/ANG-2 (panels A and B). Significant variations (P < 0.05) are indicated with an asterisk. In panel A, small and large asterisks referred to VEGFR-1 and TIE-2 expression respectively.
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pcbi.1004050.g004: Experimental validation of in silico predicted treatments using ivdTEM.TEM differentiated in vitro were exposed to the treatments predicted in silico and their changes in TIE-2 and VEGFR-1 expression (A) and pro-angiogenic activity (B) measured by flow cytometry and in vitro angiogenesis sprouting assay respectively. The impact of inhibitory treatments was examined on ivdTEM previously treated with TNF-α/PlGF/ANG-2 (panels A and B). Significant variations (P < 0.05) are indicated with an asterisk. In panel A, small and large asterisks referred to VEGFR-1 and TIE-2 expression respectively.

Mentions: As predicted, the TNF-α/ANG-2/PlGF combined treatment induced TIE-2 and VEGFR-1 expression (Fig. 4A) and increased their proangiogenic activity (Fig. 4B). Importantly, this combined treatment induced TIE-2 and VEGFR-1 expression and TEM pro-angiogenic activity more efficiently than PlGF/TNF-α (Fig. 4A) and PlGF or ANG-2 single treatments (Fig. 2A and B). These results validate our in silico prediction and reveal the synergistic effect of TIE-2, VEGFR-1 and TNF-α pathways in controlling TEM pro-angiogenic activity.


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

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 HA, Stevenson BJ, Rüegg C, Coukos G, Delaloye JF, Xenarios I, Doucey MA - PLoS Comput. Biol. (2015)

Experimental validation of in silico predicted treatments using ivdTEM.TEM differentiated in vitro were exposed to the treatments predicted in silico and their changes in TIE-2 and VEGFR-1 expression (A) and pro-angiogenic activity (B) measured by flow cytometry and in vitro angiogenesis sprouting assay respectively. The impact of inhibitory treatments was examined on ivdTEM previously treated with TNF-α/PlGF/ANG-2 (panels A and B). Significant variations (P < 0.05) are indicated with an asterisk. In panel A, small and large asterisks referred to VEGFR-1 and TIE-2 expression respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359163&req=5

pcbi.1004050.g004: Experimental validation of in silico predicted treatments using ivdTEM.TEM differentiated in vitro were exposed to the treatments predicted in silico and their changes in TIE-2 and VEGFR-1 expression (A) and pro-angiogenic activity (B) measured by flow cytometry and in vitro angiogenesis sprouting assay respectively. The impact of inhibitory treatments was examined on ivdTEM previously treated with TNF-α/PlGF/ANG-2 (panels A and B). Significant variations (P < 0.05) are indicated with an asterisk. In panel A, small and large asterisks referred to VEGFR-1 and TIE-2 expression respectively.
Mentions: As predicted, the TNF-α/ANG-2/PlGF combined treatment induced TIE-2 and VEGFR-1 expression (Fig. 4A) and increased their proangiogenic activity (Fig. 4B). Importantly, this combined treatment induced TIE-2 and VEGFR-1 expression and TEM pro-angiogenic activity more efficiently than PlGF/TNF-α (Fig. 4A) and PlGF or ANG-2 single treatments (Fig. 2A and B). These results validate our in silico prediction and reveal the synergistic effect of TIE-2, VEGFR-1 and TNF-α pathways in controlling TEM pro-angiogenic activity.

Bottom Line: Angiogenesis plays a key role in tumor growth and cancer progression.In silico predicted perturbations were validated experimentally using 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.

View Article: PubMed Central - PubMed

Affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus