Initiation of Colorectal Cancer: Where do the Two Hits Hit?

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 ?rst hits. Indeed, at the ?rst glance, short-lived differentiated cells cannot sustain a mutation longenough for the second hit to occur, because of the constantapoptosis/renewal process in epithelial tissues. Using a straightforward calculation, we show that this intuitive argument is incorrect.Our model basedon the conventional view of colon cryptarchitecture, suggests thatat least one ofthe two hits mayoccur 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 theyare short–lived. More evidence is neededto understandthe 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.