Page 301 - 20dynamics of cancer

14 Cell Lineage

History

The trillions of cells in a human slowly but steadily accumulate heritable
change. Those heritable changes evolve in a spatially mosaic way. A few
tissue patches may be advanced, poised to pass the next step to disease.
Other tissue patches may be in an early stage, apparently normal but
silently one step closer to malfunction.
Cancer progresses through heritable change to cells. Those heritable
changes pass down cell lineages. To understand progression means to
understand cell lineage history, and how different cell lineages interact.
New genetic technologies will soon provide vastly greater resolution
in the measurement of heritable changes in cells: changes in DNA se-
quence, changes in DNA methylation, and changes in histone structure.
Those new data will allow study of progression in terms of cell lineage
history.
The first section discusses the reconstruction of cell lineage history
from measurements of heritable changes in cells. The present studies
remain crude, but hint at what will come. Variation in DNA methylation
or repeated microsatellite sequences indicates the amount of heritable
diversity among cells. Greater diversity suggests a longer time since the
cells shared a common ancestor and a longer time in which the tissue has
maintained independent cell lineages. By contrast, less diversity implies
a shorter time to a common ancestor, perhaps caused by a recent clonal
succession from a progenitor cell.
Measures of diversity suggest that colon crypts retain independent
stem cell lineages for several years, but that clonal replacements oc-
casionally homogenize the crypts. Crypts with APC mutations retain
greater diversity, perhaps because those crypts retain independent lin-
eages for relatively longer periods of time. Measures of diversity in hair
follicles suggest that the follicles renew via a hierarchy of stem cells.
The bulge region of the follicle contains ultimate stem cells that divide
rarely, seeding the base of the hair with temporary stem cells that divide
relatively frequently during each round of hair growth.
The second section analyzes how cell lineage history affects progres-
sion. Mitosis is known to be a key risk factor in cancer progression. The