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MULTISTAGE PROGRESSION 57

cancer stem cells may form the main long-term line of tumor evolution.
Some evidence suggests that cancer stem cells also occur in solid tu-
mors (Singh et al. 2004; Dean et al. 2005). Phylogenetic analyses will
eventually provide a clearer picture of cell lineage history and evolution
in tumors.

MULTIPLE LINEAGES

Figure 3.5c shows the ancestry splitting into two groups soon after
the initial change that started progression. Two or more distinct lin-
eages could occur if the different lineages followed independent path-
ways in progression, and the cells from the distinct lineages did not
compete directly. Alternatively, the two lineages may provide synergis-
tic stimulation in progression; for example, each lineage could provide
complementary growth signals to its partner.
Distinct lineages may also arise independently, for example, one mu-
tation originating in a stromal cell and a second mutation originating in
an epithelial cell. Synergistic signaling between the progressive stromal
and epithelial lines could play an important role in some cases. Mueller
and Fusenig (2004) review several examples in which genetic changes
in stromal cells appear to play a key role in progression. See Kim et al.
(2006) for a recent demonstration of how progression in gastrointestinal
epithelial tissue depends on interactions with stromal cells.

PHYLOGENETIC POSITION OF MIGRANT CELLS AND METASTASES
Consider two contrasting patterns. Migrant cells may arise only from
the dominant cell lineage in late-stage localized tumors. In this case,
different colonists and the primary tumor would have a common cel-
lular ancestor a short time back. Alternatively, migrant cells may arise
at different stages of tumor development or from different lineages in
late-stage tumors. In this case, the time back to common ancestors
for colonist cells and the cells in the primary tumor would be variable;
metastases derived from colonists would be genetically heterogeneous.
Other phylogenetic patterns are possible: for example, a cancer stem cell
lineage in the primary tumor may be numerically rare but nonetheless
be the progenitor of both local and distant cell lines.
Although much has been written about which cells give rise to metas-
tases, few data exist with regard to lineage history (e.g., Bonsing et al.