The intestinal epithelium is the first line of defense again
The intestinal epithelium is the first line of defense against pathogens and noxious agents and exerts a range of physiological activities, including digestion and Penciclovir synthesis of nutrients. The intestinal wall consists of a series of finger shaped protrusions called villi and invaginations known as crypts of Lieberkuhn, where intestinal stem cells are located. The intestinal mucosa is constantly renewed, and new intestinal cells provided by pluripotent intestinal cells located at the bottom of intestinal crypts are replaced every 3–5 days. Subsequently, cells migrate towards the top of the intestinal villi changing their gene signature and metabolism from a proliferative to a differentiative pattern leading them to assume the molecular and physiologic characteristics of their final lineage: absorptive, enteroendocrine, Gobleth and Paneth cells (D'Errico and Moschetta, 2008). Cell migration from the intestinal crypt to villus involves the activity of specific transcription factors retrieving compartment-specific gene expression signature (Escaffit et al., 2006). Finally, intestinal cells acquire their final physiological function once they reach their appropriate localization. One of the most important genes in this respect is the caudal-related homeobox transcription factor (CDX2), which stands as one of the major regulatory factors controlling intestinal cell differentiation (Montgomery et al., 1999). In several human colon cancer cell lines, it has been shown to induces the transcription of several genes involved in cell-cell or cell-extracellular matrix interaction, such as E-cadherin (Lorentz et al., 1997) and claudin-2 (Sakaguchi et al., 2002), and intestine specific genes such as Mucin 2 (Yamamoto et al., 2003), and sucrose isomaltase (Boudreau et al., 2002). Once their life span is over, intestinal cells at the top of the villi undergo apoptosis and are shedded into the intestinal lumen. Orchestration of this fine balance between proliferation, migration, differentiation, cell death and definition of the physiologic potential of every intestinal cell has not been fully elucidated. Several pathways are indeed crucial in the continuous preservation of intestinal fitness and homeostasis. One of the primary forces involved in this process is the canonical Wnt/β-catenin signalling pathway (Clevers, 2006). Wnt is a signal transduction pathway involving proteins transducing signals into a cell through cell membrane receptors. The signalling initiates when Wnt ligands occupy their related receptor complex, consisting of a seven transmembrane domains Frizzeld receptor, and a member of the LDL receptor family, Lrp5/6. The central player of this transduction mechanism is a cytoplasmic protein, called β-catenin. In the absence of Wnt signalling, a “destruction complex”, consisting of Axin and the tumor suppressor APC, binds to β-catenin while glycogen synthase kinase 3 β (GSK3 β) and casein kinase 1 α (CK1α) ensure its phosphorylation, targeting it to proteosomal degradation. In the presence of Wnt, the degradation complex is inhibited, allowing cytosolic accumulation of β-catenin, which then associates with and coactivates the transcription factor T cell factor 4, ultimately leading to the induction of target genes involved in cell cycle regulation and proliferation (Aberle et al., 1997, Reya and Clevers, 2005). CRC pathogenesis is a progressive process including a sequence of cell mutations during progression from adenoma to carcinoma. The first and most common CRC mutation occurs in the APC gene, often followed by KRas, TP53, phosphoinositide 3-kinase (PI3K) and transforming growth factor β (TGFβ). Heterozygous germline mutations of the APC gene, leading to β-catenin accumulation, cause FAP, a syndrome characterized by the occurrence of several colonic polyps already at a young age (Kinzler and Vogelstein, 1996, Nishisho et al., 1991). ApcMin/+ mice, heterozygous for a nonsense mutation in the codon number 850 of the Apc gene, develop multiple tumors in the intestinal tract, are commonly used as a rodent model for both FAP and CRC (Leclerc et al., 2004, Su et al., 1992). Also, in sporadic cancer the mutations in the Apc gene are the triggering factor, however even if they are believed to be the initiating event in colonic tumorigenesis, the entire process from the appearance of the genetic alteration to the development of invasive cancer usually takes 5–20 years, enabling environmental factors, such as diet, to modify disease progression (Kinzler and Vogelstein, 1996).