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HISTORY OF THEORIES 61

reduces opportunities for clonal expansion. Without clonal expansion,
mutations must arise solely within a lineage of single cells.
The seventh section follows with theories for how multiple mutations
accumulate in cell lineages. Some authors emphasize hypermutation, in
which an early step of carcinogenesis reduces DNA repair efficacy or
promotes chromosomal aberrations during cell division. Once the care-
takers of genomic integrity have been damaged, subsequent changes
may accumulate relatively rapidly. Other authors emphasize competi-
tion between genetically variant cell lineages. Such selection between
variants favors clonal expansion of more aggressive cell lines. Tissue
architectures that reduce cell lineage competition provide some protec-
tion against cancer.
The eighth section extends the topic of the mutation rate. I mentioned
that, with regard to kinetics, any heritable genomic change that alters
gene expression can influence cancer progression. Recent work on epi-
genetic processes shows that heritable genomic changes often accumu-
late by DNA methylation and histone modification. Tumors frequently
have elevated rates of epigenetic change, providing another pathway to
increase the rate of progression.

4.1 Origins of Multistage Theory

Two different lines of thought developed the idea that cancer pro-
gresses through multiple stages. The first line arose from the observa-
tion that, in experimental animal studies, cancer often followed after se-
quential application of different chemical carcinogens. The second line
arose from observations on the age-onset patterns of cancer, in which
incidence often accelerates with age in a manner that suggests multiple
stages in progression.

EXPERIMENTAL CARCINOGENESIS
In the 1920s, several laboratories began to apply chemical carcinogens
to experimental animals. Deelman (1927) summarized observations in
which repeated applications of tar to skin led to a small number of tu-
mors, after which tarring was stopped. A few days later, the skin was cut
where no tumors had appeared. Most incisions developed tumors in the
scars; most such tumors were very malignant. Two distinct processes,
tarring and wounding, combined to cause aggressive cancers.