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50 CHAPTER 3

changes that occur during progression. Those facts help to guide the
formulation of appropriate hypotheses and tests.

3.6 What Physical Changes Drive Progression?
Genetic changes alter the DNA sequence composition of the genome:
mutation changes a few bases; loss of a chromosome followed by dupli-
cation of the remaining homologous copy causes loss of heterozygosity;
changes in chromosome numbers alter the number of gene copies; ge-
nomic rearrangements cause loss of genes or altered gene expression;
and epigenetic changes in methylation or chromatin structure also affect
gene expression.
Altered cells often change the signals they provide to other cells, lead-
ing to changes in gene expression, level of tissue differentiation, and
regulation of tissue growth. Changes in gene expression and tissue dy-
namics may lead to further changes in intercellular signaling and cause
successive loss of growth regulation.
Expanding tumors must acquire resources to fuel growth. This de-
mand for resources requires enhanced blood supply and an enriched
supporting connective-tissue framework, the tumor stroma (Mueller and
Fusenig 2004). Tumor growth depends on signaling between the cells in
the growing tumor and the complex, supporting stromal tissue.
Most tumors acquire many mutations and genomic alterations. Do
those genetic changes drive tumor progression, or are those genetic
changes a consequence of other processes that drive rapid mitoses and
tumorigenesis?
Several lines of evidence suggest that genetic changes drive cancer
progression (Vogelstein and Kinzler 2002). Inherited mutations lead
to cancer syndromes that often mimic sporadic (noninherited) cancers.
The inherited cases develop at a faster pace, consistent with the hypoth-
esis that pre-existing genetic alterations bypass normally rate-limiting
events in progression. In sporadic cases, certain genetic changes re-
cur in different individuals with the same tumor type. Genetic changes
sometimes happen in a more or less consistent order.
Because cancer arises in diverse ways, there will always be some ex-
ceptions to the central role of genetic change—cancer is the breakdown
of normal regulatory controls, and there are many pathways by which
complex regulation can fail. To show that alternatives to genetic change