Page 21 - 20dynamics of cancer

6 CHAPTER 1

incidence and acceleration curves for 21 common cancers. I include
in the Appendix detailed plots comparing incidence between the 1970s
and 1990s, and comparing incidence between the USA, Sweden, England,
and Japan. I also compare incidence between males and females for the
major cancers.
I continue Chapter 2 with summaries of incidence of major child-
hood cancers and of inherited cancers. I finish with a description of
how chemical carcinogens alter age-specific incidence. Taken together,
this chapter provides a comprehensive introduction to the observations
of cancer incidence, organized in a comparative way that facilitates anal-
ysis of the factors that determine incidence.
Chapter 3 introduces cancer progression as a sequence of failures
in components that regulate cells and tissues. I review the different
ways in which the concept of multistage progression has been used in
cancer research. I settle on progression in the general sense of devel-
opment through multiple stages, with emphasis on how rates of failure
for individual stages together determine the observed incidence curve.
I then describe multistage progression in colorectal cancer, the clearest
example of distinct morphological and genetical stages in tumor de-
velopment. Interestingly, colorectal cancer appears to have alternative
pathways of progression through different morphological and genetic
changes; the different pathways are probably governed by different rate
processes.
The second part of Chapter 3 focuses on the kinds of physical changes
that occur during progression. Such changes include somatic mutation,
chromosomal loss and duplication, genomic rearrangements, methy-
lation of DNA, and changes in chromatin structure. Those physical
changes alter key processes, resulting, for example, in a reduced ten-
dency for cell suicide (apoptosis), increased somatic mutation and chro-
mosomal instability, abrogation of cell-cycle checkpoints, enhancement
of cell-cycle accelerators, acquisition of blood supply into the develop-
ing tumor, secretion of proteases to digest barriers against invasion of
other tissues, and neglect of normal cellular death signals during mi-
gration into a foreign tissue. I finish with a discussion of how changes
accumulate over time, with special attention to the role of evolving cell
lineages throughout the various stages of tumor development.
Chapter 4 analyzes the history of theories of cancer incidence. I start
with the early ideas in the 1920s about multistage progression from