WntPCatenin Signaling in Cancer

Given the critical and pleiotropic roles of Wnts, it is not surprising that perturbations in Wnt signaling have been implicated in a range of human disorders, especially cancer (Clevers 2006b; Logan and Nusse 2004; Moon et al. 2004). Activating mutations in the canonical Wnt pathway ultimately lead to stabilization and nuclear accumulation of P-catenin. Nuclear P-catenin is the hallmark of activated canonical Wnt signaling, and its nuclear accumulation can be clearly observed in cancer cells (Bienz and Clevers 2003). By binding to Tcf/Lef transcription factors, hyperactive P-catenin turns on a genetic program sufficient to initiate development of a multitude of different tumor types, primarily of gastrointestinal origin (Giles et al. 2003; Lustig and Behrens 2003; Polakis 2000).

A series of elegant genetic studies in mice has established that Wnt/P-catenin signaling plays a fundamental role in controlling normal epithelial physiology of the intestine, most notably self-renewal of crypt stem cells (Clarke 2006; Pinto and Clevers 2005; Reya and Clevers 2005). Several Wnts and Wnt receptors are indeed expressed in various compartments of the intestine (Gregorieff et al. 2005). Among four Tcf/Lef family members, Tcf4 is prominently expressed throughout life in the intestinal epithelium. Strikingly, in neonatal mice lacking Tcf4, the differentiated villus epithelium appears normal, but the crypt stem-cell compartment in the small intestine is mostly depleted (Korinek et al. 1998). Therefore, it appears that Tcf4 mediates transformation of gut epithelial cells upon P-catenin activation. Viral or transgenic expression of Dickkopf 1 (Dkk1), a secreted Wnt antagonist, in this tissue results in markedly reduced proliferation of intestinal crypts, further supporting the crucial role of canonical Wnt signaling in regulating the maintenance of crypt stem/progenitor cells (Kuhnert et al. 2004; Pinto et al. 2003). In contrast, inducible inactivation of APC in the adult mouse intestine leads to rapid nuclear accumulation of P-catenin and repopulation of villi by crypt progenitor-like cells that fail to migrate and differentiate (Sansom et al. 2004). In addition to maintaining the pro-liferative crypt compartment, this signaling pathway promotes maturation of Paneth cells localized at the base of crypts (van Es et al. 2005). These observations highlight the physiological importance of the Wnt/P-catenin pathway in intestinal development and homeostasis.

Wnt/P-catenin signaling was initially linked to cancer formation when the APC tumor suppressor was found to be mutated in inherited familial adenomatous poly-posis (FAP) (Kinzler et al. 1991; Kinzler and Vogelstein 1996; Nishisho et al. 1991) and sporadic colorectal tumors (Kinzler and Vogelstein 1996; Korinek et al. 1997; Morin et al. 1997). FAP patients inherit one mutant APC allele and acquire a somatic mutation in the second APC allele at low frequency in their intestinal epithelial cells. These patients typically develop hundreds to thousands of colorec-tal adenomas, and some of those eventually progress to malignant adenocarcino-mas. These APC mutations typically yield truncated APC proteins that are no longer able to degrade P-catenin, followed by accumulation of P-catenin in the nucleus (Korinek et al. 1997; Morin et al. 1997). This results in inappropriate constitutive activation of P-catenin target genes, promoting the formation of benign adenoma or polyps. Of note, around 70% of all colorectal cancers have homozygous mutations in APC (Miyaki et al. 1994; Miyoshi et al. 1992; Powell et al. 1992). Mouse models for FAP harboring similar APC truncations, such as APCMin (for multiple intestinal neoplasia), develop multiple intestinal polyps predominantly in the small intestine (Moser et al. 1990; Su et al. 1992; Taketo 2006). Unfortunately, most APC mutant animals die at the age of 4-5 months due to anemia resulting from the heavy tumor load in the small intestine even before adenomatous polyps progress into metastatic adenocarcinomas. Nonetheless, these mouse models have become invaluable and powerful tools for studying the underlying mechanisms of colorectal tumorigenesis.

Approximately 10% of colorectal tumors carry activating mutations in the P-catenin gene (Miller et al. 1999; Polakis 2000). These mutations typically affect the

N-terminal region of P-catenin containing the highly conserved serine (S)/threonine (T) residues, which are sequentially phosphorylated by CKIa (S45) and then by GSK3 (S33, S37 and T41) for proteasomal degradation (Liu et al. 2002; Polakis 2002). Consequently, P-catenin becomes refractory to degradation and its nuclear levels rise, resulting in activation of target genes by the Tcf/P-catenin complex. More compelling evidence for the involvement of P-catenin signaling in intestinal tumor formation came from transgenic mouse models that conditionally express a stabilized form of P-catenin (Harada et al. 1999). When activated in the intestinal epithelium, these mice develop a large number of adenomatous polyps highly similar to those in APC mutant mice, demonstrating that activation of P-catenin signaling is sufficient for tumor formation. Moreover, frequent mutations in P-catenin have been detected in a wide range of tumor types, including malignant melanomas (Rubinfeld et al. 1997), hepatocellular carcinomas (de La Coste et al. 1998; Miyoshi et al. 1998), ovarian carcinomas (Gamallo et al. 1999; Palacios and Gamallo 1998) and Wilms' tumors (Koesters et al. 1999; Maiti et al. 2000).

Besides APC and P-catenin, mutations in the scaffold protein Axin and its close homolog Axin2 (Behrens et al. 1998) have been reported in several types of cancers, including colorectal tumors and hepatocellular carcinomas (Giles et al. 2003; Polakis 2000; Segditsas and Tomlinson 2006). In addition to these mutations in intracellular signaling components, multiple tumor types display loss of expression of the secreted Wnt antagonists sFRPs and WIF1 due to epigenetic silencing by hypermethylation (Mazieres et al. 2004; Rubin et al. 2006; Suzuki et al. 2004). Regardless of which component is misregulated, the common outcome resulting from these mutations is the stabilization of the key player P-catenin and the subsequent formation of nuclear Tcf/P-catenin complexes, causing uncontrolled tran-scriptional activation, the hallmark of cancer cells.

The Wnt/P-catenin pathway is considered to be crucial not only for cancer initiation, but also for cancer progression. Inhibition of P-catenin signaling by a dominant negative form of Tcfs that lack P-catenin-binding domain results in a rapid G1 arrest in colorectal cancer cell lines (Tetsu and McCormick 1999; van de Wetering et al. 2002). Furthermore, loss of P-catenin decreases tumor growth rates in colorectal carcinoma xenograft models (Green et al. 2001; Kim et al. 2002). These findings suggest that the high proliferative capacity of late-stage colon cancer cells remains heavily dependent on P-catenin signaling activity.

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