A pharmacologically based multiscale mathematical model of angiogenesis and its use in investigating the efficacy of a new cancer treatment strategy.
Tumor angiogenesis is the process by which new blood vessels are formed and enhance the oxygenation and growth of tumors. As angiogenesis is recognized as being a critical event in cancer development, considerable efforts have been made to identify inhibitors of this process. Cytostatic treatments that target the molecular events of the angiogenesis process have been developed, and have met with some success. However, it is usually difficult to preclinically assess the effectiveness of targeted therapies, and apparently promising compounds sometimes fail in clinical trials. We have developed a multiscale mathematical model of angiogenesis and tumor growth. At the molecular level, the model focuses on molecular competition between pro- and anti-angiogenic substances modeled on the basis of pharmacological laws. At the tissue scale, the model uses partial differential equations to describe the spatio-temporal changes in cancer cells during three stages of the cell cycle, as well as those of the endothelial cells that constitute the blood vessel walls. This model is used to qualitatively assess how efficient endostatin gene therapy is. Endostatin is an anti-angiogenic endogenous substance. The gene therapy entails overexpressing endostatin in the tumor and in the surrounding tissue. Simulations show that there is a critical treatment dose below which increasing the duration of treatment leads to a loss of efficacy. This theoretical model may be useful to evaluate the efficacy of therapies targeting angiogenesis, and could therefore contribute to designing prospective clinical trials.
Billy
Frédérique
F
Université de Lyon, F-69000 Lyon, France. billy@biomserv.univ-lyon1.fr
Ribba
Benjamin
B
Saut
Olivier
O
Morre-Trouilhet
Hélène
H
Colin
Thierry
T
Bresch
Didier
D
Boissel
Jean-Pierre
JP
Grenier
Emmanuel
E
Flandrois
Jean-Pierre
JP
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D042682:Angiopoietins / Q000378:metabolism; D043169:Endostatins / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010101:Oxygen Consumption / Q000502:physiology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D042682:Angiopoietins; D043169:Endostatins; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A