Page 267 - 20dynamics of cancer

252 CHAPTER 12

mitosis, the DNA duplex splits, each strand acting as a template for repli-
cation to produce a new complementary strand. Most mutations during
replication probably arise on the newly synthesized strand. Under a
program of asymmetric cell division, a stem lineage could reduce its
mutation rate if each stem cell division segregated the oldest template
strands to the daughter destined to remain in the stem lineage and the
newer strands to the daughter destined for the short-lived transit lin-
eage. Recent evidence supports this hypothesis of strand segregation in
stem cell lineages.
The fifth section outlines how tissue compartments prevent compe-
tition between cellular lineages. In tissues such as the intestine and
skin, the spatial architecture restricts lineal descendants of stem cells
to a very narrow region. From a lineage perspective, each compartment
limits the local population size and defines a separate parallel line of
descent and evolution. An expanding clone, perhaps one step along in
carcinogenesis, cannot normally grow beyond its compartmental bound-
aries, thus limiting the target number of cells for the accumulation of
subsequent mutations.

12.1 Background

TISSUE DEMOGRAPHY AND THE DISTRIBUTION OF TUMORS
Roughly 90% of cancers arise as carcinomas in epithelial (surface) tis-
sues. The epithelium may be the external surface of an organ, such as
the skin or outer lining of the intestine, or internal surfaces of the blad-
der, prostate, breast, and so on. The other 10% of cancers arise mostly
as leukemias (blood) and sarcomas (connective tissues, bone, etc.).
Cairns (1975) listed the tissue distributions from the Danish Cancer
Registry, as shown in Table 12.1. Peto (1977) estimated that for fatal
cancers in Britain, 20% derive from sex-specific epithelial cells (breast,
prostate, ovary), 70% derive from other epithelial cells (lung, intestine,
skin, bladder, pancreas, etc.), and 10% derive from non-epithelial cells
(blood, bone, connective tissues, etc.).
The age-specific rate of cell division explains part of the relative risk
for different tissues. Rare childhood cancers concentrate in tissues that
undergo cell division early in life followed by relative cellular quiescence
(see Section 2.3). Common adult-onset cancers occur in surface epithelia
that renew throughout life, such as in the skin and intestine.