IJE Advance Access originally published online on September 20, 2006
International Journal of Epidemiology 2006 35(5):1165-1167; doi:10.1093/ije/dyl192
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© The Author 2006; all rights reserved.
Commentary |
Commentary: Carcinogenesis as Darwinian evolution? Do the math!
Departments of Radiology and Applied Mathematics, University of Arizona, AZ, USA
E-mail: rgatenby{at}uph.org
The transition from normal tissue to invasive cancer is a multistep, multipath process in which increasingly malignant cellular populations emerge over time1–3 generally coincident with accumulating genomic mutations. This is often described as ‘somatic evolution’4,5 because it appears formally analogous to Darwinian processes in nature. While this conceptual model is well accepted, the interactions of phenotypic properties with environmental selection forces that determine individual fitness and cellular proliferation remain ill-defined. Furthermore, the language of evolution is often employed in carcinogenesis without full explanation. For example, a typical description of carcinogenesis proposes that random mutations ‘confer a selective growth advantage’ resulting in clonal expansion and subsequent tumor growth. However, precisely how a genomic change alters the phenotype and how a phenotypic trait interacts with environmental growth constraints and selection factors to promote proliferation remains vague.
Many interesting and important controversies remain unresolved within the Darwinian model of carcinogenesis. For example, tumor evolution is often portrayed as a linear sequence of genomic mutations and epigenetic changes synchronous with progressive drift of cellular populations from normal through premalignant lesions to invasive cancer.6 This approach, however, while useful conceptually and pedagogically, is highly simplified ignoring, for example, the stochastic nature of mutations, mitigating intracellular processes such as the chaperone function of heat shock proteins, and extracellular factors such as the potential influence of microenvironmental selection factors.
Similarly, the role of the mutator phenotype remains unclear. Loeb and others7 hypothesize an increased mutation rate due to defects in chromosomal stability or DNA repair pathways is necessary as a forcing function to produce the number of genomic changes required for evolution of invasive cancer. This assumes the background mutation rate is insufficient to allow the necessary carcinogenic mutations to accumulate in the human life-span. The role of the mutator phenotype is supported by observation of large numbers of mutations in most cancer cells8 and increased mutation rates in early colon and esophageal cancers.9,10
However, the mutator hypothesis has been criticized as ‘cell-centric’ and incomplete. Tomlinson, Rubin, and others cite11,12 empirical evidence and mathematical models to demonstrate normal mutation rates are sufficient for tumor evolution in microenvironments generating strong clonal selection. Furthermore, Bissell and co-workers13–16 have published a number of studies showing microenvironmental factors such as the extracellular matrix (ECM) and admixed normal cell populations alter tumor cell proliferation independent of permanent genomic change. In fact, they find, in some stages of somatic evolution, the environment plays a greater role than mutagenesis. Finally, the mutator hypothesis does not typically incorporate epigenetic phenomenon such as DNA methylation and acetylation or intracellular factors such as heat shock proteins that can maintain phenotypic robustness in the face of genomic heterogeneity.
Thus, while the conceptual model of cancer as somatic evolution is appealing and well accepted, we are far from understanding the actual dynamics governing the Darwinian interactions of altered cellular genotypes with phenotypic expression and environmental selection forces. In large part, these limitations reflect an absence of quantitative models to serve as frameworks of understanding to organize extant data, integrate new information, and stimulate new empirical studies. Indeed, it seems clear that carcinogenesis is governed by complex, non-linear processes and, for this reason, the multistep, multiyear, multipath transformation of normal cells to invasive cancer will not be understood fully without development of appropriate biologically informed quantitative models.17,18
In this issue Vineis and Berwick19 use mathematical methods developed in evolutionary biology to clarify the dynamics of carcinogenesis. They join a number of investigators11,12,20 who have used a range of quantitative techniques to various components of somatic evolution of the malignant phenotype. Their work is admirable for its firm anchoring in the biology of cancer as well as its focus on clinically relevant problems. Their results demonstrate the importance of the mutator phenotype in accelerating the evolutionary rate—findings that are consistent with those of other investigators. In addition, they demonstrate successfully the critical role of selection forces in the environment providing an approach that integrates both cellular and extracellular factors. Perhaps the most interesting component of their work is the application of modeling to cancer epidemiology. It is critical to keep in mind that cancer remains a leading cause of death in the western world and that tumor prevention, after all, is ultimately the goal of carcinogenesis modeling. While much additional work will be necessary to translate the results of quantitative modeling into clinical medicine, this is an important first step.
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