Initiation of colorectal cancer: where do the two hits hit?

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.