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MULTISTAGE PROGRESSION 37

The sixth section focuses on the physical changes during progression.
Such changes include somatic mutation, chromosomal loss and dupli-
cation, genomic rearrangements, changes in chromatin structure and
methylation of DNA, and altered gene expression.
The seventh section lists the key processes that change in progres-
sion. These changes include reduced tendency for cell suicide (apop-
tosis), increased somatic mutation and chromosomal instability, abro-
gation of cell-cycle checkpoints, enhancement of cell-cycle accelerators,
acquisition of blood supply into the developing tumor, secretion of pro-
teases to digest barriers against invasion of other tissues, and neglect
of normal cellular death signals during migration into a foreign tissue.
The eighth section examines the pattern by which changes accumulate
over time. The major rate-limiting changes may accumulate sequentially
within a single dominant tumor cell lineage. Alternatively, different cell
lineages may progress via different pathways, leading to a tumor with
distinct cell lines that diverged early in progression. In distant metas-
tases, the colonizing migrant cells may all derive from a single dominant
cell lineage in a late-stage localized tumor. By contrast, metastatic mi-
grants may emerge from different developmental stages of the primary
tumor or from different cell lineages within the primary tumor, causing
genetically distinct metastases. In general, cell lineage histories play a
key role in understanding the nature of progression.

3.1 Terminology

Tumors develop by progression through a series of stages. Experi-
mental studies that apply carcinogens to animals typically distinguish
initiation as starting the first stages in development and promotion as
stimulating the following stages (Berenblum 1941). The initiator chem-
icals often cause mutation; the promoter chemicals often increase cell
division (Lawley 1994). The word progression in experimental studies is
usually confined to the final developmental stages of cancer that follow
promotion.
In natural tumors, there may sometimes be stages corresponding to
initiation and promotion, but those stages can be highly variable, dif-
ficult to discern, and poor descriptors for particular stages in develop-
ment (Iversen 1995). In all cases, progression nicely describes progress