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Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers. Activation of this pathway is caused by genetic mutations that stabilize the β-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer factor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription factors (referred to collectively as LEF/TCFs) to activate transcription of target genes. Target genes such as MYC, CCND1, MMP7 and TCF7 (refs. 5-9) are normally expressed in colon tissue, so it has been proposed that abnormal expression levels or patterns imposed by β-catenin/TCF complexes have a role in tumor progression. We report here that LEF1 is a new type of target gene ectopically activated in colon cancer. The pattern of this ectopic expression is unusual because it derives from selective activation of a promoter for a full-length LEF1 isoform that binds β-catenin, but not a second, intronic promoter that drives expression of a dominant-negative isoform. β-catenin/TCF complexes can activate the promoter for full-length LEF1, indicating that in cancer high levels of these complexes misregulate transcription to favor a positive feedback loop for Wnt signaling by inducing selective expression of full-length, β-catenin-sensitive forms of LEF/TCFs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Levamisole (LMS) has immunomodulatory activity, stimulates the immune system of healthy, normal volunteers and has been proposed previously as a colon cancer preventive agent. Methods: Patients with a history of colonic polyps who are at increased risk of colon cancer received LMS in a placebo-controlled, double-blinded clinical trail with crossover design. Primary endpoints were immunologic and included flow cytometry of peripheral blood mononuclear cells (PBMCs), measurement of interferon-γ copy number (IGCN) in PBMCs, and an ex vivo serum immune assay. Results: No differences were seen in the expression of multiple antigens by flow cytometry pre- and post-LMS. The IGCN partitioned subjects into two distinct groups defined by a γ-distribution which had a differential response to LMS. Those with low basal IGCN had a lower percentage of CD25 expressing PBMCs and responded to low dose LMS by producing more PBMC-derived interferon-γ and increasing the expression of CD25 and two NK cell markers, CD16 and CD56. In contrast, subjects with a high basal IGCN responded to low dose LMS with a reduction in PBMC-derived interferon-γ and a decrease in the expression of CD25. Conclusions: In aggregate, these responses suggest that LMS may act as an immunostimulatory agent for one group, those with low basal IGCN, and as an immunosuppressive agent for the other. LMS may not be an optimal agent for most patients with colonic polyps and should be avoided in patients with normal immune function. IGCN may be useful as an immunologic surrogate endpoint biomarker in future cancer prevention trials with immunomodulatory agents. [Copyright &y& Elsevier]