Abstract
In this paper, we review multi-scale models of solid tumour growth and discuss a middle-out framework that tracks individual cells. By focusing on the cellular dynamics of a healthy colorectal crypt and its invasion by mutant, cancerous cells, we compare a cell-centre, a cell-vertex and a continuum model of cell proliferation and movement. All models reproduce the basic features of a healthy crypt: cells proliferate near the crypt base, they migrate upwards and are sloughed off near the top. The models are used to establish conditions under which mutant cells are able to colonize the crypt either by top-down or by bottom-up invasion. While the continuum model is quicker and easier to implement, it can be difficult to relate system parameters to measurable biophysical quantities. Conversely, the greater detail inherent in the multi-scale models means that experimentally derived parameters can be incorporated and, therefore, these models offer greater scope for understanding normal and diseased crypts, for testing and identifying new therapeutic targets and for predicting their impacts.
References
Alarcón T., Byrne H. M.& Maini P. K. . 2003A cellular automaton model for tumour growth in inhomogeneous environment. J. Theor. Biol 225, 257-274(doi:10.1016/S0022-5193(03)00244-3). Crossref, PubMed, ISI, Google ScholarBarker N., 2009Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608-611(doi:10.1038/nature07602). Crossref, PubMed, ISI, Google ScholarBienz M. . 2005β-catenin:a pivot between cell adhesion and Wnt signalling. Curr. Biol 15, 64-67(doi:10.1016/j.cub.2004.12.058). Crossref, PubMed, ISI, Google ScholarByrne H. M., Owen M. R., Alarcón T., Murphy J.& Maini P. K. . 2006Modelling the response of vascular tumours to chemotherapy:a multiscale approach. Math. Model. Methods Appl. Sci 16, 1219-1241(doi:10.1142/S0218202506001522). Crossref, ISI, Google ScholarDeutsch A.& Dormann S. . 2005Cellular automaton modeling of biological pattern formation:characterization, applications, and analysisBoston, MABirkhäuser. Google ScholarDrasdo D.& Loeffer M. . 2001Individual-based models to growth and folding in one-layered tissues:intestinal crypts and early development. Nonlinear Anal 47, 245-256(doi:10.1016/S0362-546X(01)00173-0). Crossref, ISI, Google ScholarFerlay J., Autier P., Boniol M., Heanue M., Colombet M.& Boyle P. . 2007Estimates of the cancer incidence and mortality in Europe in 2006. Ann. Oncol. 18, 581(doi:10.1093/annonc/mdl498). Crossref, PubMed, ISI, Google ScholarFozard J. A., Jensen O. E., Byrne H. M.& King J. R. . 2009Continuum approximations of individual-based models for multicellular systems. Math. Med. Biol 27, 39-74(doi:10.1093/imammb/dqp015). Crossref, PubMed, ISI, Google ScholarGaspar C.& Fodde R. . 2004APC dosage effects in tumorigenesis and stem cell differentiation. Int. J. Dev. Biol 48, 377-386(doi:10.1387/ijdb.041807cg). Crossref, PubMed, ISI, Google ScholarGlazier J. A.& Graner F. . 1993Simulation of the differential adhesion driven rearrangement of biological cells. Phys. Rev. E 47, 2128-2154(doi:10.1103/PhysRevE.47.2128). Crossref, PubMed, ISI, Google ScholarGreenspan H. P. . 1976On the growth and stability of cell cultures and solid tumors. J. Theor. Biol. 56, 2(doi:10.1016/S0022-5193(76)80054-9). Crossref, ISI, Google ScholarHonda H., Yamanaka H.& Dan-Sohkawa M. . 1984A computer simulation of geometrical configurations during cell division. J. Theor. Biol 106, 423-435(doi:10.1016/0022-5193(84)90039-0). Crossref, PubMed, ISI, Google ScholarJemal A., Siegel R., Ward E., Hao Y., Xu J.& Thun M. J. . 2009Cancer statistics, 2009. CA:Cancer J. Clin 59, 225(doi:10.3322/caac.20006). Crossref, PubMed, ISI, Google ScholarKim Y., Stolarska M. A.& Othmer H. G. . 2007A hybrid model for tumor spheroid growth in vitro I:theoretical development and early results. Math. Model. Methods Appl. Sci. 17, 1773(doi:10.1142/S0218202507002479). Crossref, ISI, Google ScholarLamprecht S. A.& Lipkin M. . 2002Migrating colonic crypt epithelial cells:primary targets for transformation. Carcinogenesis 23, 1777-1780(doi:10.1093/carcin/23.11.1777). Crossref, PubMed, ISI, Google ScholarLushnikov P. M., Chen N.& Alber M. . 2008Macroscopic dynamics of biological cells interacting via chemotaxis and direct contact. Phys. Rev. E 78, 61904(doi:10.1103/PhysRevE.78.061904). Crossref, ISI, Google ScholarMartins M. L., Ferreira S. C.& Vilela M. J. . 2007Multiscale models for the growth of avascular tumors. Phys. Life Rev. 4, 128-156(doi:10.1016/j.plrev.2007.04.002). Crossref, ISI, Google ScholarMcDonald S. A., Preston S. L., Greaves L. C., Leedham S. J., Lovell M. A., Jankowski J. A., Turnbull D. M.& Wright N. A. . 2006Clonal expansion in the human gut:mitochondrial DNA mutations show us the way. Cell Cycle 5, 808-811. Crossref, PubMed, ISI, Google ScholarMcDougall S. R., Anderson A. R. A., Chaplain M. A. J.& Sherratt J. A. . 2002Mathematical modelling of flow through vascular networks:implications for tumour-induced angiogenesis and chemotherapy strategies. Bull. Math. Biol 64, 673-702(doi:10.1006/bulm.2002.0293). Crossref, PubMed, ISI, Google ScholarMeineke F. A., Potten C. S.& Loeffer M. . 2001Cell migration and organization in the intestinal crypt using a lattice-free model. Cell Prolif. 34, 253-266(doi:10.1046/j.0960-7722.2001.00216.x). Crossref, PubMed, ISI, Google ScholarMerks R. M. H.& Glazier J. A. . 2005A cell-centered approach to developmental biology. Physica A 352, 113-130(doi:10.1016/j.physa.2004.12.028). Crossref, ISI, Google ScholarMurray P. J., Edwards C. M., Tindall M. J.& Maini P. K. . 2009From a discrete to a continuum model of cell dynamics in one dimension. Phys. Rev. E 80, 031912(doi:10.1103/PhysRevE.80.031912). Crossref, ISI, Google ScholarNagai T.& Honda H. . 2001A dynamic cell model for the formation of epithelial tissues. Phil. Mag. B 81, 699-719(doi:10.1080/13642810108205772). Crossref, Google ScholarOwen M. R., Alarcón T., Maini P. K.& Byrne H. M. . 2009Angiogenesis and vascular remodelling in normal and cancerous tissues. J. Math. Biol 58, 689-722(doi:10.1007/s00285-008-0213-z). Crossref, PubMed, ISI, Google ScholarPatel A. A., Gawlinsky E. T., Lemieux S. K.& Gatenby R. A. . 2001Cellular automaton model of early tumour growth and invasion:the effects of native tissue vascularity and increased anaerobic tumour metabolism. J. Theor. Biol 213, 315-331(doi:10.1006/jtbi.2001.2385). Crossref, PubMed, ISI, Google ScholarPitt-Francis J., 2009Chaste:a test-driven approach to software development for biological modelling. Comput. Phys. Commun 180, 2452-2471(doi:10.1016/j.cpc.2009.07.019). Crossref, ISI, Google ScholarPreston S. L., 2003Bottom-up histogenesis of colorectal adenomas:origin in the monocryptal adenoma and initial expansion by crypt fission. Cancer Res 63, 3819-3825. PubMed, ISI, Google ScholarPreziosi L.& Tosin A. . 2009Multiphase and multiscale trends in cancer modelling. Math. Model. Nat. Phenom 4, 1-11(doi:10.1051/mmnp/20094301). Crossref, ISI, Google ScholarSansom O. J., 2004Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18, 1385-1390(doi:10.1101/gad.287404). Crossref, PubMed, ISI, Google ScholarSausedo R. A., Smith J. L.& Schoenwolf G. C. . 1997Role of nonrandomly oriented cell division in shaping and bending of the neural plate. J. Compar. Neurol 381, 473-488. Crossref, PubMed, ISI, Google ScholarSchnell S., Grima R.& Maini P. K. . 2007Multiscale modeling in biology. Am. Scient. 95, 134-142. Crossref, Google ScholarShirinifard A., Gens J. S., Zaitlen B. L., Poplawski N. J., Swat M.& Glazier J. A. . 20093D multi-cell simulation of tumor growth and angiogenesis. PLoS ONE 4, 7190(doi:10.1371/journal.pone.0007190). Crossref, ISI, Google ScholarSmallbone K., Gatenby R. A., Gillies R. J., Maini P. K.& Gavaghan D. J. . 2007Metabolic changes during carcinogenesis:potential impact on invasiveness. J. Theor. Biol 244, 703-713(doi:10.1016/j.jtbi.2006.09.010). Crossref, PubMed, ISI, Google ScholarSunter J. P., Appleton D. R., Dé Rodriguez M. S., Wright N. A.& Watson A. J. . 1979A comparison of cell proliferation at different sites within the large bowel of the mouse. J. Anat 129, 833-842. PubMed, ISI, Google ScholarTaylor R. W., 2003Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest 112, 1351-1360. Crossref, PubMed, ISI, Google Scholarvan Leeuwen I. M. M., Byrne H. M., Jensen O. E.& King J. R. . 2007Elucidating the interactions between the adhesive and transcriptional functions of β-catenin in normal and cancerous cells. J. Theor. Biol 247, 77-102(doi:10.1016/j.jtbi.2007.01.019). Crossref, PubMed, ISI, Google Scholarvan Leeuwen I. M. M., 2009An integrative computational model for intestinal tissue renewal. Cell Prolif 42, 617-636(doi:10.1111/j.1365-2184.2009.00627.x). Crossref, PubMed, ISI, Google ScholarZheng X., Wise S. M.& Cristini V. . 2005Nonlinear simulation of tumor necrosis, neo-vascularization and tissue invasion via an adaptive finite-element/level-set method. Bull. Math. Biol 67, 211-259(doi:10.1016/j.bulm.2004.08.001). Crossref, PubMed, ISI, Google Scholar


