An evolutionary model for initiation, promotion, and progression in carcinogenesis

  • Authors: T. L. Vincent, R. A. Gatenby
  • View Affiliations

  • Published online on: Tuesday, April 1, 2008
  • Pages: 729-737
  • DOI: 10.3892/ijo.32.4.729

Abstract

Human carcinogenesis is a multistep process in which epithelial cells progress through a series of premalignant phenotypes until an invasive cancer emerges. Extensive experimental observations in carcinogenesis have demonstrated this process can be divided into three general eras: initiation, promotion, and progression. However, this empirically derived, tissue-level explanation of carcinogenesis has not been reconciled with the step-wise genotypic and phenotypic changes encompassed in evolutionary paradigms such as the Feoron-Vogelstein diagram. Here, we analyze an evolutionary model of cellular dynamics that defines mutual interactions of cellular and subcellular events and tissue level changes in tumor growth and morphology. Results are expressed using an adaptive landscape that illustrates the evolutionary potential of cells that allow them to adapt to specific microenvironmental selection forces. It is shown that normal epithelial cells have a novel adaptive landscape that permits coexistence of normal cellular populations but also allows invasion by mutant phenotypes. Subsequent cancer evolution is possible due to a relaxation of tissue growth constraints (as mediated by cell-cell and cell-extracellular matrix interactions) and adaptations in response to perturbations in microenvironmental substrate concentrations (due to separation of evolving tumor cells from their blood supply by an intact basement membrane). Simulations, based on the dynamic model, produce three distinct stages of carcinogenesis that are consistent with the initiation, promotion, and progression stages observed experimentally. The simulations provide insight into the underlying cellular and microenvironmental dynamics that govern these empirical observations and suggest novel prevention strategies that may be tested experimentally.
Journal Cover

April 2008
Volume 32 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

2012 Impact Factor: 2.657
Ranked #31/196 Oncology
(total number of cites)

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APA
Vincent, T., & Gatenby, R. (2008). An evolutionary model for initiation, promotion, and progression in carcinogenesis. International Journal of Oncology, 32(4), 729-737.
MLA
Vincent, and R. Gatenby. "An evolutionary model for initiation, promotion, and progression in carcinogenesis." International Journal of Oncology International Journal of Oncology 32.4 (2008): 729-737.
Chicago
Vincent, and R. Gatenby. "An evolutionary model for initiation, promotion, and progression in carcinogenesis." International Journal of Oncology International Journal of Oncology 32 no. 4 (2008): 729-737.