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MULTISTAGE PROGRESSION 51

play a primary role, one must formulate and test quantitative hypothe-
ses about how those nongenetic changes alter age-specific incidence.

3.7 What Processes Change during Progression?

I maintain my focus on rate processes that limit progression and in-
fluence age-specific incidence. However, we do not know exactly which
processes play key roles in the dynamics of progression, and different
cancers vary widely in their characteristics. So, I will provide a sample
of potential issues to set the stage for formulating quantitative hypothe-
ses in later chapters. I emphasize processes that influence cellular birth
and death, processes that generate variation in cells and tissues, and
processes that select the successful tumor variants (Hanahan and Wein-
berg 2000).

ANTI-APOPTOSIS AND ABROGATION OF PROGRAMMED CELL DEATH
Cells kill themselves when they cannot repair genetic damage, when
they do not receive tissue-specific survival signals that match their own
cell type, or when they receive death signals from immune cells (Kroe-
mer 2004). Cellular suicide—apoptosis and alternative pathways of pro-
grammed cell death—protects tissues from uncontrolled growth. Ge-
netic changes that abrogate the normal cell death response commonly
occur in tumors.

HYPERMUTATION AND CHROMOSOMAL INSTABILITY
Cells in most tumors have widespread genomic changes in chromo-
some number and arrangement (Rajagopalan et al. 2003). Those changes
often arise from increases in double-strand DNA breaks or failure to re-
pair such breaks, causing chromosomal instability. Tumors that have
lost particular DNA repair pathways may have many mutations of the
particular kind normally fixed by the lost repair system.
DNA repair systems monitor genetic damage. Detected damage in-
duces repair or apoptosis: cell death and DNA repair are intimately as-
sociated (Bernstein et al. 2002). Increased mutation or chromosomal
instability often first requires abrogation of apoptosis; otherwise, ge-
netic damage leads to cell death rather than the accumulation of genetic
change.