Effects of a grape-supplemented diet on proliferation and Wnt signaling in the colonic mucosa are greatest for those over age 50 and with high arginine consumption.

A diet rich in fruits and vegetables, and a grape-derived compound, resveratrol, have been linked to a reduced incidence of colon cancer. In vitro and in vivo, resveratrol suppresses Wnt signaling, a pathway constitutively activated in over 85 % of colon cancers.Thirty participants were placed on a low resveratrol diet and subsequently allocated to one of three groups ingesting 1/3-to-1 lb (0.

A novel signaling pathway regulates colon cancer angiogenesis through Norrin.

Norrin binds to the frizzled-4 receptor, stimulating canonical Wnt signaling. We investigate here the role of colorectal cancer (CRC) produced Norrin in endothelial cell growth, motility, and blood vessel formation, as well as the expression of the Norrin signaling pathway components in the CRC tumor microenvironment. Norrin conditioned medium produced by CRC cell line CaCO2 transfected with Norrin expression construct increased endothelial cell motility.

Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment.

Background: Wnt signaling in the colon cancer tumor microenvironment (TME) may affect cancer biologic properties including invasion and metastatic dissemination. Prior reports have suggested that the expression of select frizzled (Fz) receptors may be altered in cancers and in the TME.

Methods: Colon cancer, colonic adenoma and normal colonic mucosal specimens were obtained under institutional review board approval and analyzed for the expression of Fz1 and Fz2 by confocal fluorescent immunohistochemistry and Wnt-specific membrane array.

Expression of the Wnt antagonist Dickkopf-3 is associated with prognostic clinicopathologic characteristics and impairs proliferation and invasion in endometrial cancer.

Objective: Emerging evidence implicates the Wnt antagonist Dickkopf-3 (Dkk3) as a tumor suppressor and potential biomarker in solid tumors. We investigated whether Dkk3 plays an important role in the carcinogenesis of endometrial cancer (EC).

Methods: We analyzed Dkk3 mRNA expression via real-time RT-PCR in twenty-seven human primary EC tissues, and six matched normal endometrial controls.

Granulocyte-macrophage stimulating factor (GM-CSF) increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy.

Background: Advanced cancer and chemotherapy are both associated with immune system suppression. We initiated a clinical trial in patients receiving chemotherapy for metastatic colorectal cancer to determine if administration of GM-CSF in this setting was immunostimulatory.

Methods: Between June, 2003 and January, 2007, 20 patients were enrolled in a clinical trial (NCT00257322) in which they received 500 ug GM-CSF daily for 4 days starting 24 hours after each chemotherapy cycle.

Lymphoid enhancer-binding factor 1, a representative of vertebrate-specific Lef1/Tcf1 sub-family, is a Wnt-beta-catenin pathway target gene in human endothelial cells which regulates matrix metalloproteinase-2 expression and promotes endothelial cell invasion.

Background: Wnt signaling is activated in many types of cancer and normal physiological processes. Various Wnt-related secreted factors may influence angiogenesis both in the tumor microenvironment and in normal tissues by direct action on endothelial cells. The mechanism of this Wnt action in angiogenesis is not well defined.

Role of canonical Wnt signaling in endometrial carcinogenesis.

While the role of Wnt signaling is well established in colorectal carcinogenesis, its function in gynecologic cancers has not been elucidated. Here, we describe the current state of knowledge of canonical Wnt signaling in endometrial cancer (EC), and its implications for future therapeutic targets. Deregulation of the Wnt/β-catenin signaling pathway in EC occurs by inactivating β-catenin mutations in approximately 10-45% of ECs, and via downregulation of Wnt antagonists by epigenetic silencing.

Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer.

Context: Resveratrol exhibits colon cancer prevention activity in animal models; it is purported to have this activity in humans and inhibit a key signaling pathway involved in colon cancer initiation, the Wnt pathway, in vitro.

Design: A phase I pilot study in patients with colon cancer was performed to evaluate the effects of a low dose of plant-derived resveratrol formulation and resveratrol-containing freeze-dried grape powder (GP) on Wnt signaling in the colon. Eight patients were enrolled and normal colonic mucosa and colon cancer tissue were evaluated by Wnt pathway-specific microarray and quantitative real-time polymerase chain reaction (qRT-PCR) pre- and post-exposure to resveratrol/GP.

Coculture methodologies for the study of Wnt signals.

In vivo, responses to extracellular Wnt ligands are context dependent; the temporal characteristics and intensity of the signal are critical in determining the target cell response. In general, Wnt ligand-induced differentiation in mammalian cells requires several days of exposure. In order to better characterize Wnt-induced signaling in vitro, side-by-side and partitioned cocultures can be utilized.

In situ hybridization to evaluate the expression of Wnt and frizzled genes in mammalian tissues.

In situ hybridization can be utilized to specifically define the expression of genes and to determine their localization in complex mammalian tissues. The expression of specific members of the Wnt ligand and frizzled receptor families of molecules can be defined using an antisense RNA probe that will specifically hybridize with messenger RNA (mRNA) in the tissue to form a double-stranded product. The double-stranded product can then be detected microscopically by identifying digoxigenin groups that are attached to the probe during its synthesis.

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention.

Resveratrol is a bioflavonoid which is known to inhibit cell proliferation and induce apoptosis in cancer cell lines at concentrations above 50 muM. It also has colon cancer prevention activity in mouse models and possibly in humans. We have examined the effects of low concentrations of resveratrol on a specific signaling pathway, the Wnt pathway, which is activated in over 85% of sporadic colon cancers.

Regulation of norrin receptor frizzled-4 by Wnt2 in colon-derived cells.

Background: Norrin is a potent Wnt pathway ligand. Aberrant activation of this signaling pathway can result in colon tumors but the role of norrin-based signaling in the genesis of colon cancer, and its relationship to activation of the pathway by traditional Wnt ligands, is not defined.

Results: Fresh normal human colon tissue and all the cell lines studied expressed mRNA for Fz4, LRP5 and norrin, except Colo205 which lacked Fz4 expression.

Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking ErbB2 (her-2/neu) overexpression.

This study examines the role of LEF1, a component of the Wnt signaling pathway, in human breast and murine mammary carcinoma and its relationship to ErbB2 (her-2/neu) expression. Mammary tissue and tumors from 5 different Wnt pathway-activated transgenic mouse strains and 5 different ErbB2 pathway-activated transgenic mouse strains were studied for the amount and distribution of expression of beta-catenin and LEF1. Fourteen samples of human infiltrating ductal breast cancer arising from a background of ductal carcinoma in situ (DCIS) were analyzed for LEF1, estrogen and progesterone receptor (ER and PR) and her-2/neu expression.

Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma.

The Wnt genes encode a family of related, secreted proteins which initiate a signal cascade upon binding to cell surface receptor molecules. The signaling pathway has been shown to be critical for normal growth and development in model organisms and is implicated in the genesis of numerous human cancers. Wnt proteins regulate mammary development in the mouse but their precise role in normal breast development and malignant transformation in humans remains poorly defined.