2013, 10(1): 167-184. doi: 10.3934/mbe.2013.10.167

A structural model of the VEGF signalling pathway: Emergence of robustness and redundancy properties

1. 

INRIA, Project-team NUMED, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, 69007 Lyon Cedex 07, France, France, France, France

Received  July 2012 Revised  September 2012 Published  December 2012

The vascular endothelial growth factor (VEGF) is known as one of the main promoter of angiogenesis - the process of blood vessel formation. Angiogenesis has been recognized as a key stage for cancer development and metastasis. In this paper, we propose a structural model of the main molecular pathways involved in the endothelial cells response to VEGF stimuli. The model, built on qualitative information from knowledge databases, is composed of 38 ordinary differential equations with 78 parameters and focuses on the signalling driving endothelial cell proliferation, migration and resistance to apoptosis. Following a VEGF stimulus, the model predicts an increase of proliferation and migration capability, and a decrease in the apoptosis activity. Model simulations and sensitivity analysis highlight the emergence of robustness and redundancy properties of the pathway. If further calibrated and validated, this model could serve as tool to analyse and formulate new hypothesis on th e VEGF signalling cascade and its role in cancer development and treatment.
Citation: Floriane Lignet, Vincent Calvez, Emmanuel Grenier, Benjamin Ribba. A structural model of the VEGF signalling pathway: Emergence of robustness and redundancy properties. Mathematical Biosciences & Engineering, 2013, 10 (1) : 167-184. doi: 10.3934/mbe.2013.10.167
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show all references

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[8]

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[13]

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[17]

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[18]

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[19]

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[20]

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[21]

J. Folkman, Tumor angiogenesis factor,, Cancer Research, 34 (1974).

[22]

J. Folkman, New perspectives in clinical oncology from angiogenesis research,, European Journal of Cancer (Oxford, 32 (1996).

[23]

F. M. Gabhann and A. S. Popel, Systems biology of vascular endothelial growth factors,, Microcirculation, 15 (2008), 715. doi: 10.1080/10739680802095964.

[24]

G. Gasparini, R. Longo, M. Fanelli and B. A. Teicher, Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions,, Journal of Clinical Oncology, 23 (2005), 1295. doi: 10.1200/JCO.2005.10.022.

[25]

H. P. Gerber, A. McMurtrey, J. Kowalski, M. Yan, B. A. Keyt, V. Dixit and N. Ferrara, Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway,, Journal of Biological Chemistry, 273 (1998), 30336. doi: 10.1074/jbc.273.46.30336.

[26]

F. Graner and J. A. Glazier, Simulation of biological cell sorting using a two-dimensional extended Potts model,, Physical Review Letters, 69 (1992), 2013. doi: 10.1103/PhysRevLett.69.2013.

[27]

M. Hatakeyama, S. Kimura, T. Naka, T. Kawasaki, N. Yumoto, M. Ichikawa, J. H. Kim, K. Saito, M. Saeki, M. Shirouzu, S. Yokoyama and A. Konagaya, A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling,, Biochemical Journal, 373 (2003), 451. doi: 10.1042/BJ20021824.

[28]

B. S. Hendriks, F. Hua and J. R. Chabot, Analysis of mechanistic pathway models in drug discovery: p38 pathway,, Biotechnology Progress, 24 (2008), 96. doi: 10.1021/bp070084g.

[29]

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[30]

C. Huang, K. Jacobson and M. D. Schaller, MAP kinases and cell migration,, Journal of Cell Science, 117 (2004), 4619. doi: 10.1242/jcs.01481.

[31]

R. K Jain, Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy,, Nature Medicine, 7 (2001), 987. doi: 10.1038/nm0901-987.

[32]

R. K Jain, Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy,, Science, 307 (2005), 58. doi: 10.1126/science.1104819.

[33]

H. Kitano, Computational systems biology,, Nature, 420 (2002), 206. doi: 10.1038/nature01254.

[34]

H. Kitano, Cancer robustness: tumour tactics,, Nature, 426 (2003), 125. doi: 10.1038/426125a.

[35]

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[36]

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[38]

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[40]

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J. Ma and D. J. Waxman, Combination of antiangiogenesis with chemotherapy for more effective cancer treatment,, Molecular Cancer Therapeutics, 7 (2008), 3670. doi: 10.1158/1535-7163.MCT-08-0715.

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