Preneoplastic lesion growth driven by the death of adjacent normal stem cells

Dennis L. Chao, J. Thomas Eck, Douglas E. Brash, Carlo Maley, E. Georg Luebeck

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Clonal expansion of premalignant lesions is an important step in the progression to cancer. This process is commonly considered to be a consequence of sustaining a proliferative mutation. Here, we investigate whether the growth trajectory of clones can be better described by a model in which clone growth does not depend on a proliferative advantage. We developed a simple computer model of clonal expansion in an epithelium in which mutant clones can only colonize space left unoccupied by the death of adjacent normal stem cells. In this model, competition for space occurs along the frontier between mutant and normal territories, and both the shapes and the growth rates of lesions are governed by the differences between mutant and normal cells' replication or apoptosis rates. The behavior of this model of clonal expansion along a mutant clone's frontier, when apoptosis of both normal and mutant cells is included, matches the growth of UVB-induced p53-mutant clones in mouse dorsal epidermis better than a standard exponential growth model that does not include tissue architecture. The model predicts precancer cell mutation and death rates that agree with biological observations. These results support the hypothesis that clonal expansion of premalignant lesions can be driven by agents, such as ionizing or nonionizing radiation, that cause cell killing but do not directly stimulate cell replication.

Original languageEnglish (US)
Pages (from-to)15034-15039
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number39
DOIs
StatePublished - Sep 30 2008
Externally publishedYes

Fingerprint

Stem Cells
Clone Cells
Growth
Nonionizing Radiation
Apoptosis
Mutation Rate
Ionizing Radiation
Epidermis
Computer Simulation
Cell Death
Epithelium
Mutation
Mortality
Neoplasms

Keywords

  • Clonal expansion
  • Computer simulation
  • Skin cancer
  • TP53
  • UVB

ASJC Scopus subject areas

  • General

Cite this

Preneoplastic lesion growth driven by the death of adjacent normal stem cells. / Chao, Dennis L.; Thomas Eck, J.; Brash, Douglas E.; Maley, Carlo; Georg Luebeck, E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 39, 30.09.2008, p. 15034-15039.

Research output: Contribution to journalArticle

Chao, Dennis L. ; Thomas Eck, J. ; Brash, Douglas E. ; Maley, Carlo ; Georg Luebeck, E. / Preneoplastic lesion growth driven by the death of adjacent normal stem cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 39. pp. 15034-15039.
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