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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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Tie-2 and VEGFR-1, and Ang-2 and PIGF represent attractive targets in breast cancer (A) Correlation of Ang-2 and PlGF and CD14 protein expression levels in the tumor with tumor size in 17 patients.The significance of their linear correlation is shown by Pearson r and p values. (B-F) Survival analysis. The good prognostic effect of the lower expression of CD14, ANG-2 and PIGF (B) is reflected by the clear separation from the over expression group on the Kaplan-Meier plot, with a P value of 0.0257 from a Log-rank test (F), whereas only ANG-2 (C) or PIGF (D) combined with CD14 separate worse lower and over expression groups, suggesting a synergistic effect of ANG-2 and PIGF to promote CD14-mediated angiogenesis and the corresponding impact on patient relapse free survival. (E) Shows the survival curve of lower expression patients for the three cases.
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pcbi.1004050.g007: Tie-2 and VEGFR-1, and Ang-2 and PIGF represent attractive targets in breast cancer (A) Correlation of Ang-2 and PlGF and CD14 protein expression levels in the tumor with tumor size in 17 patients.The significance of their linear correlation is shown by Pearson r and p values. (B-F) Survival analysis. The good prognostic effect of the lower expression of CD14, ANG-2 and PIGF (B) is reflected by the clear separation from the over expression group on the Kaplan-Meier plot, with a P value of 0.0257 from a Log-rank test (F), whereas only ANG-2 (C) or PIGF (D) combined with CD14 separate worse lower and over expression groups, suggesting a synergistic effect of ANG-2 and PIGF to promote CD14-mediated angiogenesis and the corresponding impact on patient relapse free survival. (E) Shows the survival curve of lower expression patients for the three cases.

Mentions: To this end we analyzed a dataset including tumor expression profiles and clinical data of 1809 breast cancer patients [50] and compared two subsets of patients: those with lowest and highest expression values for ANG-2, PIGF and CD14 (as TEM marker), using as threshold the first and fourth quartile respectively. These quartiles were computed independently for each gene, and the two groups of selected patients resulted from the intersection of them all (Fig. 7B-F). The Kaplan-Meier plot showed a clear separation between patients with low (n = 40) and high (n = 62) expression for these three genes, with a p-value of 0.0257 derived from log-rank analysis (Fig. 7B and F). Interestingly, we observed that the same analysis repeated for patients with high and low levels of ANG-2 and CD14 or PIGF and CD14 (and not for the remaining gene) resulted on p-values not statistically significant (0.0587 and 0.521 respectively, Fig. 7C-E), suggesting that the synergistic effect of the corresponding pathways is required to have a significant impact on the survival.


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)

Tie-2 and VEGFR-1, and Ang-2 and PIGF represent attractive targets in breast cancer (A) Correlation of Ang-2 and PlGF and CD14 protein expression levels in the tumor with tumor size in 17 patients.The significance of their linear correlation is shown by Pearson r and p values. (B-F) Survival analysis. The good prognostic effect of the lower expression of CD14, ANG-2 and PIGF (B) is reflected by the clear separation from the over expression group on the Kaplan-Meier plot, with a P value of 0.0257 from a Log-rank test (F), whereas only ANG-2 (C) or PIGF (D) combined with CD14 separate worse lower and over expression groups, suggesting a synergistic effect of ANG-2 and PIGF to promote CD14-mediated angiogenesis and the corresponding impact on patient relapse free survival. (E) Shows the survival curve of lower expression patients for the three cases.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004050.g007: Tie-2 and VEGFR-1, and Ang-2 and PIGF represent attractive targets in breast cancer (A) Correlation of Ang-2 and PlGF and CD14 protein expression levels in the tumor with tumor size in 17 patients.The significance of their linear correlation is shown by Pearson r and p values. (B-F) Survival analysis. The good prognostic effect of the lower expression of CD14, ANG-2 and PIGF (B) is reflected by the clear separation from the over expression group on the Kaplan-Meier plot, with a P value of 0.0257 from a Log-rank test (F), whereas only ANG-2 (C) or PIGF (D) combined with CD14 separate worse lower and over expression groups, suggesting a synergistic effect of ANG-2 and PIGF to promote CD14-mediated angiogenesis and the corresponding impact on patient relapse free survival. (E) Shows the survival curve of lower expression patients for the three cases.
Mentions: To this end we analyzed a dataset including tumor expression profiles and clinical data of 1809 breast cancer patients [50] and compared two subsets of patients: those with lowest and highest expression values for ANG-2, PIGF and CD14 (as TEM marker), using as threshold the first and fourth quartile respectively. These quartiles were computed independently for each gene, and the two groups of selected patients resulted from the intersection of them all (Fig. 7B-F). The Kaplan-Meier plot showed a clear separation between patients with low (n = 40) and high (n = 62) expression for these three genes, with a p-value of 0.0257 derived from log-rank analysis (Fig. 7B and F). Interestingly, we observed that the same analysis repeated for patients with high and low levels of ANG-2 and CD14 or PIGF and CD14 (and not for the remaining gene) resulted on p-values not statistically significant (0.0587 and 0.521 respectively, Fig. 7C-E), suggesting that the synergistic effect of the corresponding pathways is required to have a significant impact on the survival.

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