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MULTISTAGE PROGRESSION 53

the worn chromosome ends cause double-strand DNA breaks, leading
to chromosomal rearrangements and genomic instability (Feldser et al.
2003).
Certain cells must divide many times without wearing out: the germ
cells continue on without decay; the stem cells that replenish renew-
ing epithelial tissues divide hundreds or perhaps thousands of times
over the normal human lifespan. Those cells express a special enzyme,
telomerase, that regenerates the full telomere during each replication
cycle.
Late-stage cancer cells usually express telomerase (Mathon and Lloyd
2001). Telomerase expression may occur because the original cells that
began progression were specialized to avoid senescence. Or the cancer
cell lineage may have turned on telomerase during some stage of pro-
gression. If telomerase is off during early progression, the cancer cell
lineage may develop frayed telomeres and genomic instability (Feldser
et al. 2003). That instability creates genetic variability, perhaps enhanc-
ing the opportunity to develop a more aggressive genotype. However,
the widespread chromosomal aberrations must eventually be controlled
in the cancer cell lineage by turning on expression of telomerase, oth-
erwise the lineage would probably self-destruct from genetic defects
(Frank and Nowak 2004).

RESOURCE ACQUISITION AND STROMAL ECOLOGY
Progression follows in part from genetic changes that cause loss of
control over cellular birth and death. But tumorigenesis is more complex
than just transforming particular cells by genetic change. For example,
a solid tumor cannot grow beyond 1–2mm without obtaining a blood
supply. Tumor cells acquire vasculature by angiogenesis, the process of
stimulating blood vessel growth through a tissue (Folkman 2002). Com-
plex regulatory processes control angiogenesis (Folkman 2003). In the
default state, blood vessels usually will not grow through the tissue of
a developing tumor. To progress, the tumor must overcome angiogenic
repression and stimulate the growth of a blood supply.
Signals that stimulate angiogenesis may come directly from the tu-
mor cells or by collaboration with the complex mixture of other cell
types in and around the developing tumor. Those other cells usually