Vascular phenotype identification and anti-angiogenic treatment recommendation: a pseudo-multiscale mathematical model of angiogenesis

Autor: Helen M. Byrne, Eamonn A. Gaffney, Alex Phipps, Jonathan Wagg, L.G. Hutchinson, Philip K. Maini
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Vascular Endothelial Growth Factor A
0301 basic medicine
Statistics and Probability
Angiogenesis
Cancer therapy
Angiogenesis Inhibitors
Computational biology
Models
Biological
General Biochemistry
Genetics and Molecular Biology
Angiopoietin-2
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Computer Simulation
Platelet-Derived Growth Factor
Neovascularization
Pathologic
General Immunology and Microbiology
biology
Applied Mathematics
Anti angiogenic
Endothelial Cells
Numerical Analysis
Computer-Assisted
General Medicine
Phenotype
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Modeling and Simulation
Immunology
biology.protein
Blood Vessels
Biomarker (medicine)
Identification (biology)
Pericyte
General Agricultural and Biological Sciences
Platelet-derived growth factor receptor
Zdroj: Journal of Theoretical Biology. 398
ISSN: 1095-8541
0022-5193
Popis: The development of anti-angiogenic drugs for cancer therapy has yielded some promising candidates, but novel approaches for interventions to angiogenesis have led to disappointing results. In addition, there is a shortage of biomarkers that are predictive of response to anti-angiogenic treatments. Consequently, the complex biochemical and physiological basis for tumour angiogenesis remains incompletely understood. We have adopted a mathematical approach to address these issues, formulating a spatially averaged multiscale model that couples the dynamics of VEGF, Ang1, Ang2 and PDGF, with those of mature and immature endothelial cells and pericyte cells. The model reproduces qualitative experimental results regarding pericyte coverage of vessels after treatment by anti-Ang2, anti-VEGF and combination anti-VEGF/anti-Ang2 antibodies. We used the steady state behaviours of the model to characterise angiogenic and non-angiogenic vascular phenotypes, and used mechanistic perturbations representing hypothetical anti-angiogenic treatments to generate testable hypotheses regarding transitions to non-angiogenic phenotypes that depend on the pre-treatment vascular phenotype. Additionally, we predicted a synergistic effect between anti-VEGF and anti-Ang2 treatments when applied to an immature pre-treatment vascular phenotype, but not when applied to a normalised angiogenic pre-treatment phenotype. Based on these findings, we conclude that changes in vascular phenotype are predicted to be useful as an experimental biomarker of response to treatment. Further, our analysis illustrates the potential value of non-spatial mathematical models for generating tractable predictions regarding the action of anti-angiogenic therapies.
Databáze: OpenAIRE
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