  Most cancers in humans are large, measuring centimeters in diameter, composed
of many billions of cells. An equivalent mass of normal cells would be highly
heterogeneous as a result of the mutations that occur during each cell
division. What is remarkable about cancers is their homogeneity - virtually
every neoplastic cell within a large cancer contains the same core set of
genetic alterations, with heterogeneity confined to mutations that have emerged
after the last clonal expansions. How such clones expand within the
spatially-constrained three dimensional architecture of a tumor, and come to
dominate a large, pre-existing lesion, has never been explained. We here
describe a model for tumor evolution that shows how short-range migration and
cell turnover can account for rapid cell mixing inside the tumor. With it, we
show that even a small selective advantage of a single cell within a large
tumor allows the descendants of that cell to replace the precursor mass in a
clinically relevant time frame. We also demonstrate that the same mechanisms
can be responsible for the rapid onset of resistance to chemotherapy. Our model
not only provides novel insights into spatial and temporal aspects of tumor
growth but also suggests that targeting short range cellular migratory activity
could have dramatic effects on tumor growth rates.
