This irregular TCF/LEF activation is independent of Wnt receptor activation; however, changes in the homeostasis of cell lines bearing an APC mutation as a result of the effect of different Wnt inhibitors have been described. Based on the methylation analysis of macrodissected samples, it has been described that in colorectal carcinogenesis SFRP1 promoter is epigenetically silenced. In this study, we aim to examine the protein expression and methylation patterns of myofibroblast-derived SFRP1 in NAT and CRC tissues, and to demonstrate the effect of SFRP1 protein on HCT116 CRC cell line as a potential model of paracrine inhibition of the Wnt pathway in colorectal carcinoma. Wnt signaling is a major regulator of a variety of cellular processes during Masitinib embryonic development and promotes tissue homeostasis in the adult. Wnts are secreted lipid-modified glycoproteins regulating a wide range of cellular behavior including differentiation, proliferation, migration, survival, Vorinostat polarity and stem cell self-renewal. Altered Wnt signaling may contribute to the development of several disorders including cancer. The canonical/b-catenin pathway is the most extensively studied Wnt signaling mechanism, which is triggered by Wnt binding to a member of the Frizzled receptor family and co-receptors. This results in the recruitment of Dishevelled to Frizzled and Axin to phosphorylated LRP5/6, leading to the dissociation of a b-catenin degradation complex. In the absence of Wnt this complex mediates the sequential phosphorylation of b-catenin, causing its ubiquitination and proteasomal degradation. Wnt stimulation allows the accumulation of hypophosphorylated b-catenin in the cytosol and its translocation into the nucleus, where it binds to TCF/LEF and promotes the expression of Wnt/b-catenin target genes. Constitutive activation of this pathway is commonly present in many types of cancer. Non-canonical Wnt-signaling pathways are transduced by Frizzleds and/or other Wnt receptors or co-receptors. Several non-canonical Wnt signaling mechanisms have been reported to inhibit the b-catenin pathway by decreasing b-catenin/TCF association with DNA or increasing b-catenin turnover. SFRPs comprise a family of five proteins in mammals that were first identified as antagonists of the Wnt/b-catenin pathway during embryonic development. SFRPs possess a remarkable range of biological activities, including tumor suppression. This is also strengthened by epigenetic silencing of SFRP gene expression in a wide variety of cancers, and supported by the observation that restoration of expression is suppressive of the tumor phenotype. By contrast, SFRP overexpression has been observed in some of the same malignancies. Consistent with this duality, SFRP1 showed a biphasic effect on b-catenin stabilization elicited by Wingless, increasing b-catenin protein levels at low SFRP1 concentrations, but inhibiting it at high concentrations. In different cellular contexts, SFRP1 has been shown either to increase or decrease b-catenin stabilization. Furthermore, another study suggested that SFRP1 could stimulate the Wnt/calcium pathway via Frizzled-2 independently of endogenous Wnts. Regarding field cancerization, methylation of hMLH1, CDKN2A/P16 and SFRP1 has been recently indicated to be associated with malignant transition in endometrial cancer. In our study, the apoptotic effect of SFRP1 protein was demonstrated by administering low doses of rhSFRP1 on HCT116 CRC cell line. In HCT116 cells rhSFRP1 protein caused a measurable increase in apoptosis. We investigated the role of SFRP1 regarding the stromaepithelium interaction in CRC and NAT areas. SFRP1 protein is a well-known intercellular inhibitor of Wnt pathway which regulates the epithelial proliferation as autocrine and/or paracrine signal.