DIMACS TR: 2004-54
Initiation of colorectal cancer: where do the two hits hit?
Authors: Natalia L. Komarova and Liming Wang
ABSTRACT
It is widely believed that stem cells are of special
importance for colorectal cancer initiation. The earliest event being
the inactivation of both alleles of the Adenomatous Polyposis Coli
(APC) gene, it is thought that the stem cells are the most likely
target for these two first hits. Indeed, at the first glance,
short-lived differentiated cells cannot sustain a mutation long enough
for the second hit to occur, because of the constant apoptosis/renewal
process in epithelial tissues. Using a straightforward calculation, we
show that this intuitive argument is incorrect. Our model based on the
conventional view of colon crypt architecture, suggests that at least
one of the two hits may occur in the migrating compartment. We suggest
that a possible role of differentiating cells in cancer initiation
cannot be discarded simply based on the fact that they are
short--lived. More evidence is needed to understand the cellular
origins of cancer and to identify whether or not a double hit in a
daughter cell can be ``immortalizing''. In this study we discuss
several scenarios and propose some experiments which can shed light on
these questions.
Paper Available at:
ftp://dimacs.rutgers.edu/pub/dimacs/TechnicalReports/TechReports/2004/2004-54.ps.gz
DIMACS Home Page