Page 284 - 20dynamics of cancer

STEM CELLS: TISSUE RENEWAL 269

the number of stem cells in the pool. In a symmetric mitosis, the age
of the DNA strands increases in one of the new daughter stem cells.
This increase in age can be seen on the right side of Figure 12.10a. In
a steady-state stem cell division, the top daughter that would normally
segregate to the transit lineage has templates that have ages one and two
relative to the initial template of age zero that the main stem lineage has
retained.
The lost stem cell may alternatively be replaced by a daughter transit
cell (Cairns 2002). If, for example, the most recent daughter transit cell
on the right side of Figure 12.10a reverted to a stem cell, strand age
would increase by one relative to the lost ancestral stem cell.
Mitogenesis caused by wounds, chemical carcinogens, or irritation
increases the rate of cancer progression (reviewed by Peto 1977; Cairns
1998). Presumably wounds and other forms of tissue damage often kill
stem cells; repair requires that those stem cells be replaced.
The interesting comparison is: How much of the increased risk comes
from the accumulation of mutations in the stem line caused by sym-
metric mitoses, and how much of the enhanced risk comes from an
increased rate of mitosis independently of the distinction between sym-
metry and asymmetry in DNA strand segregation?

12.5 Tissue Compartments
and Repression of Competition

The renewing epithelia of the intestine and skin have a compartmental
structure (Figures 12.4 and 12.8). Each stem cell normally contributes
only to its own compartment. This spatial restriction prevents com-
petition between stem cell lineages in different compartments (Cairns
1975).
Suppose, for example, that a mutation caused a particular stem cell
to replicate faster. That mutant lineage might take over its own com-
partment, outcompeting other stem lineages within the compartment.
But spatial restrictions would often prevent the mutant lineage from
spreading beyond its own small neighborhood. From a lineage perspec-
tive, each compartment limits the local population size and defines a
separate parallel line of descent and evolution. An expanding clone,