Page 297 - 20dynamics of cancer

282 CHAPTER 13

This optimal design, with long transit lineages and no stem lineage,
assumes that all k cells survive to the end of the required period, with
no sloughing of cells. However, the requirement for continual cell death
at epithelial surfaces imposes an additional requirement. But for now,
I am just asking about the best design in the absence of the constraint
imposed by renewal, to understand how much of tissue architecture may
be explained by natural selection among alternative designs versus how
much may be explained by the unavoidable constraints of renewal.
This first analysis suggests that natural selection favors long transit
lineages and no stem lineage. If so, then the stem-transit design may
be the consequence solely of continual cell death at the tissue surface,
which imposes a stem-transit separation by shortening the cell lineages
that lead to the sloughing of surface cells. But we should consider two
additional factors.
First, the stem lineage may have a lower mutation rate than the tran-
sit lineage. Cairns (1975) proposed that immortal stranding and high
sensitivity to DNA damage lower the stem-line mutation rate (See Sec-
tion 12.4). If the stem lineage does have a lower mutation rate than the
transit lineage, then natural selection would favor adding more cell di-
visions to the lower-risk stem line. In terms of design, this benefit of
stem divisions would lengthen the stem lineage, that is, increase n 1 in
Figure 13.5, and would shorten the higher-risk transit lineages, that is,
decrease n 2 .
Second, the transit lineage may be partially protected, because a tran-
sit cell that gets the required n carcinogenic changes may still slough
off. This benefit would favor lengthening the transit lineages, because
natural selection always tends to allocate additional divisions to those
lineages with the lowest relative risk. This particular benefit for transit
lineages works against the maintenance of a distinct, long-lived stem
line.
In summary, two factors appear to favor a stem-transit design. A
renewing tissue necessarily has continual cell death that prunes cell lin-
eages and creates a dichotomy between short and long cell lineages.
That constraint of tissue renewal may be sufficient to explain the stem-
transit design, even though, with regard to cancer risk, natural selection
often favors a more even distribution of cell lineage length. Alterna-
tively, if the stem line accrues mutations at a lower rate than the transit