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Article
Quantitative interpretation of a genetic model of carcinogenesis using computer simulations
PloS one
  • Donghai Dai, University of Iowa
  • B. Beck
  • X. Wang
  • C. Howk
  • Y. Li
Document Type
Article
Peer Reviewed
1
Publication Date
3-1-2011
NLM Title Abbreviation
Plos One
PubMed ID
21408146
DOI of Published Version
10.1371/journal.pone.0016859
Abstract

The genetic model of tumorigenesis by Vogelstein et al. (V theory) and the molecular definition of cancer hallmarks by Hanahan and Weinberg (W theory) represent two of the most comprehensive and systemic understandings of cancer. Here, we develop a mathematical model that quantitatively interprets these seminal cancer theories, starting from a set of equations describing the short life cycle of an individual cell in uterine epithelium during tissue regeneration. The process of malignant transformation of an individual cell is followed and the tissue (or tumor) is described as a composite of individual cells in order to quantitatively account for intra-tumor heterogeneity. Our model describes normal tissue regeneration, malignant transformation, cancer incidence including dormant/transient tumors, and tumor evolution. Further, a novel mechanism for the initiation of metastasis resulting from substantial cell death is proposed. Finally, model simulations suggest two different mechanisms of metastatic inefficiency for aggressive and less aggressive cancer cells. Our work suggests that cellular de-differentiation is one major oncogenic pathway, a hypothesis based on a numerical description of a cell's differentiation status that can effectively and mathematically interpret some major concepts in V/W theories such as progressive transformation of normal cells, tumor evolution, and cancer hallmarks. Our model is a mathematical interpretation of cancer phenotypes that complements the well developed V/W theories based upon description of causal biological and molecular events. It is possible that further developments incorporating patient- and tissue-specific variables may build an even more comprehensive model to explain clinical observations and provide some novel insights for understanding cancer.

Keywords
  • Cell Aging/genetics,
  • Cell Death/genetics,
  • Cell Differentiation/genetics,
  • Cell Survival/genetics,
  • Cell Transformation,
  • Neoplastic/genetics,
  • Clone Cells,
  • Computer Simulation,
  • Disease Progression,
  • Epithelial Cells/pathology,
  • Female,
  • Humans,
  • Models,
  • Genetic,
  • Neoplasm Metastasis,
  • Neoplasms/genetics,
  • Neoplastic Cells,
  • Circulating/pathology,
  • Precancerous Conditions/genetics,
  • Uterus/pathology
Published Article/Book Citation
PloS one, 6:3 (2011) pp.e16859
Citation Information
Donghai Dai, B. Beck, X. Wang, C. Howk, et al.. "Quantitative interpretation of a genetic model of carcinogenesis using computer simulations" PloS one Vol. 6 Iss. 3 (2011) p. e16859 ISSN: 1932-6203
Available at: http://works.bepress.com/donghai_dai/20/