WNT signaling in the normal intestine and colorectal cancer

Abstract

The intestinal epithelium is a self-renewing tissue that represents a unique model for studying interconnected cellular processes such as proliferation, differentiation, cell migration and carcinogenesis. This review covers work from the past decade and highlights the importance of the canonical Wnt pathway in regulating multiple aspects of intestinal homeostasis. Numerous in vivo studies combined with gene profiling experiments have shown that Wnt signaling promotes maintenance of epithelial stem cells and early progenitors by driving transcription of genes associated with proliferation. These studies also revealed strong similarities between the genetic program initiated by Wnt signals in normal crypt progenitors and in colorectal cancer cells. More recently it has become apparent that Wnts do not act alone but rather cooperate with Notch signals in maintaining progenitor cell populations. Processes associated with differentiated epithelial cells also appear to be regulated by Wnt signals. For instance, Paneth cells employ active Wnt signals for terminal differentiation. Moreover, through transcriptional regulation of members of the Eph and Ephrin families, Wnt signaling promotes compartmentalization of epithelial cells along the crypt-villus axis. The Eph/Ephrin system also operates to limit progression of colorectal cancer beyond the early stages.

Luteolin, a Bioflavonoid Inhibits Colorectal Cancer through Modulation of Multiple Signaling Pathways: A Review

“…Frequent mutations in the Wnt pathway are considered an early, important step in human CRC and are responsible for colon tumor formation in patients with familial polyposis (FAP) (Moser et al, 1990;deLau et al, 2007). The oncogenic potential of the Wnt pathway derives from β-catenin protein stabilization and relocation from the cell membrane to the nucleus, where it is recruited into T-cell factor/lymphoid enhancer factor 1 (TCF/LEF) transcriptional regulatory complexes (Fuchs et al, 2005).…”

Viral Oncogene Expression in the Stem/Progenitor Cell Compartment of the Mouse Intestine Induces Adenomatous Polyps

“…Multiple lines of evidence indicate a central role of the canonical Wnt pathway, nuclear translocation of β-catenin and activation of its downstream target genes (e.g. c-myc; (24)) in intestinal homeostasis, tumorigenesis and polyp formation (25-29). In addition, most adenocarcinomas and neoplasms of the colon show nuclear localization of β-catenin (30).…”

Mediator and human disease

“…While early surgical excision of non-invasive tumors is essentially curative, few effective treatment options are available for advanced stage disease, which carries a grave prognosis. Colon tumors arise from intestinal crypts, from whence progenitor-derived epithelial cells commence differentiation as they initiate their ascent up intestinal villi [131]. Maintenance of the crypt progenitor phenotype is dependent upon the expression of genes programmed by the canonical Wnt/β-catenin pathway, and constitutive activation of this pathway is a driving force in the immortalization of intestinal epithelia and the initiation of colon cancer [131–134].…”

“…Colon tumors arise from intestinal crypts, from whence progenitor-derived epithelial cells commence differentiation as they initiate their ascent up intestinal villi [131]. Maintenance of the crypt progenitor phenotype is dependent upon the expression of genes programmed by the canonical Wnt/β-catenin pathway, and constitutive activation of this pathway is a driving force in the immortalization of intestinal epithelia and the initiation of colon cancer [131–134]. While the upstream events in this pathway linked to signal-induced stabilization and activation of β-catenin in the cytoplasm have been deciphered in considerable detail, the mechanistic basis by which β-catenin activates gene transcription upon translocation into the nucleus is comparably poorly understood.…”