Page 286 - 20dynamics of cancer

13 Stem Cells:

Population Genetics

Heritable changes in populations of cells drive cancer progression. In
this chapter, I discuss three topics concerning population-level aspects
of cellular genetics.
The first section shows that mutations during development may con-
tribute significantly to cancer risk. In development, cell lineages expand
exponentially to produce the cells that initially seed a tissue. A sin-
gle mutation in an expanding population carries forward to many de-
scendant cells. By contrast, once the tissue has developed, each new
mutation usually remains confined to the localized area of the tissue
that descends directly from the mutated cell. Because mutations during
development carry forward to many more cells than mutations during
renewal, a significant fraction of cancer risk may be determined in the
short period of development early in life.
The second section analyzes the distinction between stem lineages
and transit lineages. To renew a tissue, cells must be continuously pro-
duced to balance the equal number of cells that die. Cell death prunes
certain cell lineages—the transit lineages—and requires that other lin-
eages continue to provide future renewal—the stem lineages. Renewal
imposes a constraint on the shape of stem and transit lineages. Within
this constraint, if the mutation rate is relatively lower in stem cells, then
relatively longer stem lineages and shorter transit lineages reduce can-
cer risk.
The third section contrasts symmetric and asymmetric mitoses in
stem cells. Each stem cell may divide asymmetrically, every division
giving rise to one daughter stem cell and one daughter transit cell. Al-
ternatively, each stem cell may divide symmetrically, giving rise to two
daughters that retain the potential to continue in the stem lineage; ran-
dom selection among the pool of excess potential stem cells reduces
the stem pool back to its constant size. With asymmetric division, any
heritable change remains confined to the independent lineage in which
it arose. With symmetric division, the random selection process causes
each heritable change eventually to disappear or to become fixed in the
stem pool; only one lineage survives over time.