Multiscale modelling of tumour growth and therapy: the influence of vessel normalisation on chemotherapy

Following the poor clinical results of antiangiogenic drugs, particularly when applied in isolation, tumour biologists and clinicians are now turning to combinations of therapies in order to obtain better results. One of these involves vessel normalisation strategies. In this paper, we investigate the effects on tumour growth of combinations of antiangiogenic and standard cytotoxic drugs, taking into account vessel normalisation. An existing multiscale framework is extended to include new elements such as tumour-induced vessel dematuration. Detailed simulations of our multiscale framework allow us to suggest one possible mechanism for the observed vessel normalisation-induced improvement in the efficacy of cytotoxic drugs: vessel dematuration produces extensive regions occupied by quiescent (oxygen-starved) cells which the cytotoxic drug fails to kill. Vessel normalisation reduces the size of these regions, thereby allowing the chemotherapeutic agent to act on a greater number of cells.

[1]  S. Dower,et al.  Response of tumour cells to hypoxia: role of p53 and NFkB. , 1998, Molecular pathology : MP.

[2]  A. Pries,et al.  Structural adaptation and stability of microvascular networks: theory and simulations. , 1998, The American journal of physiology.

[3]  James P. Keener,et al.  Mathematical physiology , 1998 .

[4]  Stanley J. Wiegand,et al.  Vascular-specific growth factors and blood vessel formation , 2000, Nature.

[5]  C J Kemp,et al.  p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. , 2001, Experimental cell research.

[6]  B. Reglin,et al.  Structural adaptation of microvascular networks: functional roles of adaptive responses. , 2001, American journal of physiology. Heart and circulatory physiology.

[7]  Chi V. Dang,et al.  Hypoxia Inhibits G1/S Transition through Regulation of p27 Expression* , 2001, The Journal of Biological Chemistry.

[8]  E. T. Gawlinski,et al.  A Cellular Automaton Model of Early Tumor Growth and Invasion: The Effects of Native Tissue Vascularity and Increased Anaerobic Tumor Metabolism , 2001 .

[9]  R K Jain,et al.  Delivery of molecular medicine to solid tumors: lessons from in vivo imaging of gene expression and function. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[10]  J. Tyson,et al.  Regulation of the eukaryotic cell cycle: molecular antagonism, hysteresis, and irreversible transitions. , 2001, Journal of theoretical biology.

[11]  A. Giaccia,et al.  p21Cip1 and p27Kip1Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest , 2001, Molecular and Cellular Biology.

[12]  Denis Noble,et al.  The IUPS human physiome project , 2002, Pflügers Archiv.

[13]  Andreas Deutsch,et al.  Cellular Automaton Models of Tumor Development: a Critical Review , 2002, Adv. Complex Syst..

[14]  A. Deutsch,et al.  Modeling of self-organized avascular tumor growth with a hybrid cellular automaton. , 2002, In silico biology.

[15]  P. Maini,et al.  A cellular automaton model for tumour growth in inhomogeneous environment. , 2003, Journal of theoretical biology.

[16]  Rakesh K Jain,et al.  Molecular regulation of vessel maturation , 2003, Nature Medicine.

[17]  Nitzan Resnick,et al.  Fluid shear stress and the vascular endothelium: for better and for worse. , 2003, Progress in biophysics and molecular biology.

[18]  P. Maini,et al.  Mathematical oncology: Cancer summed up , 2003, Nature.

[19]  E. T. Gawlinski,et al.  The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. , 2003, Cancer research.

[20]  Beverly A. Teicher,et al.  A systems approach to cancer therapy , 1996, Cancer and Metastasis Reviews.

[21]  R. Mayer,et al.  Two steps forward in the treatment of colorectal cancer. , 2004, The New England journal of medicine.

[22]  Lei Xu,et al.  Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. , 2004, Cancer cell.

[23]  H. Othmer,et al.  Mathematical modeling of tumor-induced angiogenesis , 2004, Journal of mathematical biology.

[24]  P. Maini,et al.  A mathematical model of the effects of hypoxia on the cell-cycle of normal and cancer cells. , 2004, Journal of theoretical biology.

[25]  P K Maini,et al.  A mathematical model of Doxorubicin treatment efficacy for non-Hodgkin’s lymphoma: Investigation of the current protocol through theoretical modelling results , 2005, Bulletin of mathematical biology.

[26]  Kinetics of vascular normalisation by VEGFR2 blockade governs brain tumour response to radiation: role of angiopoietin-1 and matrix metalloproteinases , 2005 .

[27]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[28]  Helen M. Byrne,et al.  A Multiple Scale Model for Tumor Growth , 2005, Multiscale Model. Simul..

[29]  Alexander R. A. Anderson,et al.  Mathematical modelling of the influence of blood rheological properties upon adaptative tumour-induced angiogenesis , 2006, Math. Comput. Model..

[30]  P. Maini,et al.  MODELLING THE RESPONSE OF VASCULAR TUMOURS TO CHEMOTHERAPY: A MULTISCALE APPROACH , 2006 .

[31]  H Rieger,et al.  Vascular network remodeling via vessel cooption, regression and growth in tumors. , 2005, Journal of theoretical biology.

[32]  S. McDougall,et al.  Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies. , 2006, Journal of theoretical biology.

[33]  Helen M. Byrne,et al.  Structural Adaptation in Normal and Cancerous Vasculature , 2007 .