Intestinal Epithelial Cell Dedifferentiation Initiates Tumorigenesis

Mutational activation of the WNT pathway results in β-catenin stabilization and induction of downstream target genes, which stimulate the expansion of crypt stem cells that have been proposed to initiate intestinal tumorigenesis. Activation of canonical NF-κB signaling by chronic inflammation or oncogenes such as KRAS has also been implicated in tumor growth and progression, but the role of NF-κB in tumor stem cells is unknown. Schwitalla and colleagues used a genetic model of intestinal tumor initiation driven by constitutively active β-catenin expression in intestinal epithelial cells (IEC). These mice exhibited expansion of proliferative crypt stem cells and loss of differentiated enterocytes, as well as a significant increase in NF-κB activity in IECs mediated in part by TNF-α. Concomitant inhibition of NF-κB signaling in this model diminished crypt expansion and expression of WNT-induced stem cell markers, resulting in prolonged survival and suggesting that NF-κB activation regulates β-catenin–dependent transcription of stem cell genes. Consistent with this idea, RelA/p65 interacted with β-catenin in IECs and augmented the binding of mutant β-catenin to stem cell gene promoters. Furthermore, constitutive NF-κB activation in IECs enhanced the activity of mutant β-catenin and accelerated the accumulation of transformed stem cells both in crypts and in the villus epithelium. These aberrant villus crypt-like foci reexpressed stem cell markers including leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), suggesting that nonstem cells may regain cancer stem cell properties through cooperative NF-κB and β-catenin signaling. Indeed, although β-catenin alone was not sufficient to induce a tumor stem cell phenotype, combined activation of WNT and KRAS promoted NF-κB–dependent dedifferentiation of Lgr5-negative villus IECs and acquisition of tumor-initiating potential. These results demonstrate that inflammatory signaling modulates the bidirectional conversion of stem cells and differentiated IECs to stimulate intestinal tumor initiation.

Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 2013;152:25–38.

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