Table 4. Computationally predicted minimal perturbations sets (MIS) required for transitioning TEM regulatory network into highly or weakly pro-angiogenic TEM.
| RTK activity inhibited | Up-regulated Inflammatory Ligand | Up-regulated VEGFR-1 ligand | Up-regulated TIE-2 ligand | ||
|---|---|---|---|---|---|
| Transition to weakly pro-angiogenic TEM | |||||
| Group 1 | |||||
| TIE-2 | TGF-β | VEGF | - | ||
| TIE-2 | TGF-β | PlGF | - | ||
| TIE-2 | TGF-β | - | ANG-1 | ||
| TIE-2 | TGF-β | - | ANG-2 | ||
| Group 2 | |||||
| VEGFR-1 | TNF-α | - | ANG-1 | ||
| VEGFR-1 | TNF-α | VEGF | - | ||
| VEGFR-1 | - | all but PlGF | - | ||
| TIE-2 and VEGFR-1 | - | - | - | ||
| Group 3 | |||||
| - | TNF-α and TGF-β | PlGF | - | ||
| - | TNF-α and TGF-β | - | ANG-1 | ||
| - | TNF-α and TGF-β | VEGF | - | ||
| Transition to highly pro-angiogenic TEM | - | TNF-α | PlGF | ANG-2 |
These two final desired cell steady states were obtained by assigning to TIE-2 and VEGFR-1 nodes a fixed polarity of either both high (highly pro-angiogenic i.e tumor TEM) or low (weakly proangiogenic i.e. blood TEM) expression levels. Computationally predicted MIS decreasing TEM pro-angiogenic activity were classified in three groups based on the receptor tyrosine kinase (RTK) inhibited and inflammatory (TGF-β or TNF-α) and angiogenic ligands up-regulated.