Biotechnology Letters

, Volume 37, Issue 3, pp 551–556 | Cite as

Tissue normalizing capacity as a key determinant of carcinogenesis: an in silico simulation

  • Wenhu Cao
Original Research Paper


A perturbed microenvironment is at the core of carcinogenesis. Here, we used a 2D cellular automata model to simulate how cancers are generated in epithelial tissue. We applied several mathematical rules to simulate tissue renewal and surrounding cell control. Under the simulation, we showed that the average value of surrounding normal cells could be an indicator for the tissue normalizing capacity (TNC). Further, we found the incidence of carcinogenesis correlated inversely with the TNC. Interestingly, we also found that multi-round mutagenesis could gradually disturb the TNC when compared to one-round mutagenesis: cancer incidence increased significantly compared to one-round mutagenesis. Our model suggests that the genetic alterations (mutations) by themselves were not sufficient to initiate cancer. The perturbation of TNC could be a key process leading to carcinogenesis.


Carcinogenesis Epithelial cancers In silico simulation Somatic mutation theory Tissue normalization Tissue organization field theory 



I thank Prof. Stuart G Baker, from Biometry Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, USA, for the critical review of the manuscript. I also thank Prof. Carlos Sonnenschein, from Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, USA, for this candid comments and careful revision of the manuscript.


  1. Alarcon T, Byrne HM et al (2003) A cellular automaton model for tumour growth in inhomogeneous environment. J Theor Biol 225:257–274CrossRefPubMedGoogle Scholar
  2. Alexander DB, Ichikawa H et al (2004) Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and Src activity. Cancer Res 64:1347–1358CrossRefPubMedGoogle Scholar
  3. Anderson ARA, Chaplain MAJ (1998) Continuous and discrete mathematical models of tumor-induced angiogenesis. Bull Math Biol 60:857–899CrossRefPubMedGoogle Scholar
  4. Baker SG, Soto AM et al (2009) Plausibility of stromal initiation of epithelial cancers without a mutation in the epithelium: a computer simulation of morphostats. BMC Cancer 9:89–99CrossRefPubMedCentralPubMedGoogle Scholar
  5. Booth BW, Boulanger CA et al (2011) The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neutransformed mammary tumor cells. Oncogene 30:679–689CrossRefPubMedCentralPubMedGoogle Scholar
  6. Boveri T (1929) The origin of malignant tumors. Williams & Wilkins, Baltimore, MD, pp 62–63Google Scholar
  7. Braakhuis BJ, Tabor MP et al (2003) A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63:1727–1730PubMedGoogle Scholar
  8. Brash D, Cairns J (2009) The mysterious steps in carcinogenesis. Br J Cancer 101:379–380CrossRefPubMedCentralPubMedGoogle Scholar
  9. Bussard KM, Boulanger CA et al (2010) Reprogramming human cancer cells in the mouse mammary gland. Cancer Res 70:6336–6343CrossRefPubMedCentralPubMedGoogle Scholar
  10. Dalerba P, Cho RW et al (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284CrossRefPubMedGoogle Scholar
  11. Ermentrout GB, Edelstein-Keshet L (1993) Cellular automata approaches to biological modelling. J Theor Biol 160:97–133CrossRefPubMedGoogle Scholar
  12. Gerard RW (1957) Units and concepts of biology. Science 125:429–433CrossRefPubMedGoogle Scholar
  13. Haas D, Ablin A et al (1988) Complete pathologic maturation and regression of stage IVS neuroblastoma without treatment. Cancer 62:818–825CrossRefPubMedGoogle Scholar
  14. Hogan C, Dupre-Crochet S et al (2009) Characterization of the interface between normal and transformed epithelial cells. Nat Cell Biol 11:460–467CrossRefPubMedGoogle Scholar
  15. Hogan C, Kajita M et al (2011) Interactions between normal and transformed epithelial cells: their contributions to tumourigenesis. Int J Biochem Cell Biol 43:496–503CrossRefPubMedGoogle Scholar
  16. Kansal AR, Torquato S et al (2000) Simulated brain tumour growth dynamics using a threedimensional cellular automaton. J Theor Biol 203:367–382CrossRefPubMedGoogle Scholar
  17. Kasemeier-Kulesa JC, Teddy JM et al (2008) Reprogramming multipotent tumor cells with the embryonic neural crest microenvironment. Dev Dyn 237:2657–2666CrossRefPubMedCentralPubMedGoogle Scholar
  18. Kenny PA, Bissell MJ (2003) Tumor reversion: correction of malignant behavior by microenvironmental cues. Int J Cancer 107:688–695CrossRefPubMedCentralPubMedGoogle Scholar
  19. LeBlond CP (1964) Classification of cell populations on the basis of their proliferative behavior. Natl Cancer Inst Monogr 14:119–150PubMedGoogle Scholar
  20. Maffini MV, Calabro JM et al (2005) Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. Am J Pathol 167:1405–1410CrossRefPubMedCentralPubMedGoogle Scholar
  21. McCullough KD, Coleman WB et al (1998) Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors. Proc Natl Acad Sci USA 95:15333–15338CrossRefPubMedCentralPubMedGoogle Scholar
  22. Mintz B, Ilmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 72:3585–3589CrossRefPubMedCentralPubMedGoogle Scholar
  23. Prehn RT (1994) Cancers beget mutations versus mutations beget cancers. Cancer Res 54:5296–5300PubMedGoogle Scholar
  24. Soto AM, Sonnenschein C (2004) The somatic mutation theory of cancer: growing problems with the paradigm? BioEssays 26:1097–1107CrossRefPubMedGoogle Scholar
  25. Stoker MG, Shearer M et al (1966) Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J Cell Sci 1:297–310PubMedGoogle Scholar
  26. Vincent JP, Fletcher AG et al (2013) Mechanisms and mechanics of cell competition in epithelia. Nat Rev Mol Cell Biol 14:581–591CrossRefPubMedGoogle Scholar
  27. Wolfram S (1984) Cellular automata as models of complexity. Nature 311:419–424CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of ResearchNanjing Red Cross Blood CenterNanjingChina

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