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HISTORY OF THEORIES 71

the cell-cycle “gatekeeper” genes and those genes that manage genetic
integrity “caretaker” genes.
A distinct line of theory focuses on the important role of tissue inter-
actions instead of the accumulation of mutations in cell lineages. For
example, Folkman (2003) emphasizes angiogenesis—the recruitment of
a blood supply to a growing tumor. In developing epithelial tumors,
the neighboring stromal tissue interacts in many ways with the primary
growth (Mueller and Fusenig 2004).
With regard to tissue interactions, perhaps the key problem concerns
the nature of rate-limiting steps in progression. For example, a primary
cell lineage that is accumulating mutations and progressing toward can-
cer may acquire a mutation that alters the neighboring stromal tissue
or attracts a blood supply. Kinzler and Vogelstein (1998) call such mu-
tations “landscapers.” Alternatively, genetic changes may arise in the
neighboring tissue rather than in the primary cell lineage that has started
toward tumor progression. Or changes in tissue may be limited by phys-
iological processes that do not derive from underlying genetic changes.
In summary, the dominant view at present focuses on accumulation
of genomic changes in one or perhaps a few cell lineages. Tissue interac-
tions, such as angiogenesis and signals from the stromal environment,
clearly influence tumorigenesis, but their relative importance compared
to genetic change in limiting the quantitative rate of progression re-
mains unknown. Finally, other types of genomic changes that regulate
gene expression may be important, such as methylation of DNA pro-
moter regions and modification of histones. I discuss below how such
genomic changes in gene regulation may influence rates of progression.
With these modern views of mutation accumulation and cancer pro-
gression in mind, I return to the problem of mutation rates. That prob-
lem influenced the development of theoretical models.

4.4 Can Normal Somatic Mutation
Rates Explain Multistage Progression?

By the 1950s, studies of age-specific incidence in humans and chem-
ical carcinogenesis in animals supported the theory that cancer pro-
gresses through multiple stages. The first quantitative theories of Nord-
ling (1953) and Armitage and Doll (1954) inferred approximately six
stages.