Cell hierarchies in colorectal cancer: focus on APC and BRAF

The Wnt-APC-β-Catenin and RAS-RAF-MAPK signaling pathways serve to maintain homeostasis in the normal intestinal epithelium. This state is characterized by an equilibrium between stemness, proliferation, differentiation and cell death [1]. Recent studies by our group [2] and by Dow et al. [3] elucidate how oncogenes and tumor suppressors influence cell hierarchies during colorectal cancer (CRC) formation in the mouse and highlight the potential of this information for future approaches to cancer therapy. A majority of CRCs are initiated by APC mutations promoting Wnt/β-Catenin activity and stem cell fate [4]. As we described already in 2012, reversible transgenic expression of oncogenic β-Catenin can switch mouse intestinal epithelium between normal and adenomatous cell hierarchies [5]. For these experiments, we used organotypic cell cultures maintaining stem, proliferative and differentiated cells. β-Catenin promoted a universal capacity for self-renewal and expression of cancer stem cell markers, similar to cultures derived from APC-/adenoma. Withdrawal of oncogenic β-Catenin re-established normal cell hierarchies driven by only few stem cells in the crypts. A new publication by Dow et al. [3] shows that reversible knockdown of APC in the intestine of mice establishes adenomatous growth in vivo, while restoration of APC results in reversion to normal cell hierarchies and tumor regression. When the authors combined reversible APC knockdown with conditional gainand loss-of-function alleles for the KRAS oncogene and the p53 tumor suppressor, respectively, invasive colon carcinoma developed. Significantly, restoration of APC resulted in complete remission and reverted colon cancer tissue to normal intestinal epithelium even in the presence of oncogenic KRAS and absence of p53. These results demonstrate a surprising ability of intestinal epithelium to regain homeostasis. In contrast to Wnt/β-Catenin, the roles of MAPK activity in the control of intestinal cell hierarchies Editorial