Elsevier

Seminars in Cancer Biology

Volume 15, Issue 6, December 2005, Pages 474-483
Seminars in Cancer Biology

Review
Natural selection in neoplastic progression of Barrett's esophagus

https://doi.org/10.1016/j.semcancer.2005.06.004Get rights and content

Abstract

Neoplasms progress to cancer through a process of natural selection. The rate of evolution, and thus progression is determined by three parameters: mutation rate, population size of the evolving neoplastic cells, and intensity of selection or rate of clonal expansion. All three parameters are reviewed in the context of Barrett's esophagus, a pre-malignant neoplasm. Although Barrett's esophagus is an ideal model for the study of neoplastic clonal evolution, similar studies may be carried out in a wide variety of human neoplasms. Evolutionary analyses provide insights for clinical management, including rates of progression to cancer and emergence of resistance to interventions.

Section snippets

Natural selection in neoplastic progression

A neoplasm is a microcosm of evolution. This fact lies at the heart of why we get cancer and why it has been so hard to cure. Within a neoplasm, mutant clones compete for space and resources [1], [2], [3], [4], [5]. Those that have a competitive advantage and are more aggressive will tend to spread in the neoplasm until a mutation produces an invasive phenotype and the neoplasm becomes malignant. Therapies add a new selective force to the neoplasm and tend to select for resistance [6], [7], [8]

Parameters of the rate of evolution

If neoplastic progression is an evolutionary process, then the rate of evolution should be associated with the rate of progression to cancer. Evolution is traditionally and most narrowly defined as changes in allele frequencies. There are three parameters that determine the rate of evolution in a neoplasm: (1) mutation rate, (2) population size, and (3) strength of selection. The faster that new mutations accumulate in a neoplasm, the faster the neoplasm will acquire all the necessary

Barrett's esophagus as a model of clonal evolution in neoplastic progression

Nowell's hypothesis of clonal evolution in neoplastic progression should apply to all neoplasms. However, it has been difficult to study in most neoplasms because either the pre-cursor lesions are not easily identified, or if they are identified, they are removed and so cannot be studied longitudinally to see how the clones evolve. Barrett's esophagus (BE) is an exception.

BE is a pre-malignant neoplastic [20] condition of the esophagus, that is the only known precursor of esophageal

Mutation rate

Mutation rates are difficult to study in humans in vivo. Most estimates of mutation rates either come from cell culture [34], [35] or the big blue mouse [36]. However, there is no doubt that BE neoplastic cells have higher mutation rates than normal tissue because a variety of genetic and epigenetic lesions have been observed in BE at higher frequencies than are observed in normal tissues.

Allelotype studies, using a sparse set of microsatellite markers scattered across the genome, have found

Population size

The size of a population is a fundamental constraint on the rate at which it can accumulate mutations and evolve. Until the mid 1970s, there were reports of BE segments growing over time [58], [59], [60]. However, since that time, such reports have virtually disappeared [61]. It may not be a coincidence that H2 blockers, the first effective acid suppression medications, were introduced in the mid 1970s. Today, in the vast majority of cases, the length of the Barrett's segment remains stable

Strength of selection

The strength of selection on a particular allele is best measured by the rate at which it spreads through a population. This has been difficult to measure in most neoplasms for two reasons: very few neoplasms can be tracked over time and few investigators have measured the frequency of alleles within a neoplasm by assaying multiple biopsies [20], [68].

The close association between gastroesophageal reflux and the etiology of BE suggests that under the abnormal environment of reflux, BE cells

Open problems

Neoplastic evolution is probably better understood in BE than any other human solid neoplasm, and is summarized in Fig. 1. However, there are many unsolved mysteries that require further study.

Conclusions

Barrett's esophagus has proven a fruitful model system of human neoplastic progression in which to test Nowell's hypothesis in vivo. All of the necessary components of natural selection in a neoplasm have been confirmed in BE including somatic variation, heritability of that variation, and differences in relative fitness of the clones due to that variation. The introduction of evolutionary theory to cancer biology provides a useful set of quantitative analyses and explanations for neoplastic

Acknowledgements

This work was supported by NIH grants P01 CA91955 and K01 CA89267-02. Thanks to Thomas Paulson for helpful comments and suggestions.

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