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HISTORY OF THEORIES 77

in cell division and age-specific incidence. Moolgavkar and Knudson fo-
cused on extending the two-hit theories with clonal expansion to fit the
age-incidence curves of both childhood and adult cancers.
Cairns (1975) wrote the key paper on cell lineage shape in epithelial
tissues. He emphasized three factors that reduce mutation accumula-
tion and the risk of cancer.
First, renewal of epithelial tissue from stem cells creates a linear cel-
lular history that reduces opportunities for multiple mutations to accu-
mulate in a lineage. Normally, each stem cell division gives rise to one
stem cell that remains at the base of the epithelium and one transit cell.
The transit cell divides a limited number of times, producing cells that
move up from the basal layer and eventually slough off from the sur-
face. The stem lineage renews the tissue and survives over time. Thus,
accumulation of somatic mutations occurs mainly in the stem lineage.
Mutations in transit cells usually are discarded as the transit cells die at
the surface.
Recent studies of human epidermal tissue suggest that the skin re-
news from relatively slowly dividing basal stem cells that give rise to
rapidly dividing transit lineages, each transit lineage undergoing 3–5
rounds of replication before sloughing from the surface (Janes et al.
2002). Studies of gastrointestinal tissues estimate 4–6 rounds of divi-
sion by transit lineages (Bach et al. 2000). Sell (2004) reviews the nature
of stem cells in other tissues.
Second, stem cells may have reduced mutation rates compared with
other somatic cells. In each asymmetric stem cell division, the stem lin-
eage may retain the original DNA templates, with all new DNA copies
segregating to the transit lineage. If most mutations occur in the pro-
duction of new DNA strands, then most mutations would segregate to
the transit lineage, and the stem lineage would accumulate fewer muta-
tions per cell division (Merok et al. 2002; Potten et al. 2002; Smith 2005;
Karpowicz et al. 2005). In addition, stem cells may be particularly prone
to apoptosis in response to DNA damage, killing themselves rather than
risking repair of damage (Potten 1998; Bach et al. 2000).
Third, compartmental organization of tissues reduces the opportu-
nity for competition and selection between lineages. In the epidermis
and intestine, each stem lineage clonally renews a small, well-defined
sector of tissue. The whole tissue spans numerous separate, noncom-
7
peting cell lineages. The colon has about 10 such compartments, called