Page 266 - 20dynamics of cancer

12 Stem Cells:

Tissue Renewal

Tissue renewal determines the rate of cell division. In many tissues,
renewal derives from rare stem cells. In this chapter, I discuss how
mitotic rate and lineal descent from stem cells set the relative risk of
cancer.
The first section provides background on tissue renewal and cancer.
About 90% of human cancers arise in epithelial tissues. Epithelial layers
in certain organs, such as the intestine and skin, renew continuously
throughout life. Cancer incidence in renewing tissues rises sharply with
age. By contrast, childhood cancers concentrate in tissues that divide
rapidly early in life but relatively little later in life. In general, the age-
specific rate of cell division explains part of the relative risk for different
tissues at different ages.
The second section describes the shape of cell lineages in renewing
tissues. Many tissues that renew frequently have a clear hierarchy of
cell division and differentiation. Rare stem cells divide occasionally,
each division giving rise on average to one replacement stem cell for
future renewal and to one transit cell. The transit cell undergoes multi-
ple rounds of division to produce the various short-lived, differentiated
cells. New stem cell divisions continually replace the lost transit cells.
I review the stem-transit architecture of cell lineages in blood forma-
tion (hematopoiesis), in gastrointestinal and epidermal renewal, and in
sex-specific tissues such as the sperm, breast, and prostate.
The third section discusses the important distinction between sym-
metric and asymmetric stem cell divisions. In symmetric divisions, the
two daughter cells have an equal chance to remain a stem cell or dif-
ferentiate into a transit cell. To maintain a pool of N stem cells in a
niche, each stem cell division produces on average one new stem cell
and one new transit cell; the fate of each cell is determined randomly.
In asymmetric divisions, differentiation happens in a determined way:
one particular daughter cell remains a stem cell, and the other differen-
tiates into a transit cell.
The fourth section analyzes how symmetric versus asymmetric stem
cell divisions affect the accumulation of mutations over time. In every