Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin.
Summary of "Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin."
Constitutive activation of Wnt/β-catenin signaling in cancer results from mutations in pathway components, which frequently coexist with autocrine Wnt signaling or epigenetic silencing of extracellular Wnt antagonists. Among the extracellular Wnt inhibitors, the secreted frizzled-related proteins (SFRPs) are decoy receptors that contain soluble Wnt-binding frizzled domains. In addition to SFRPs, other endogenous molecules harboring frizzled motifs bind to and inhibit Wnt signaling. One of such molecules is V3Nter, a soluble SFRP-like frizzled polypeptide that binds to Wnt3a and inhibits Wnt signaling and expression of the β-catenin target genes cyclin D1 and c-myc. V3Nter is derived from the cell surface extracellular matrix component collagen XVIII. Here, we used HCT116 human colon cancer cells carrying the ΔS45 activating mutation in one of the alleles of β-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced β-catenin stabilization. Consequently, V3Nter reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis, as shown by decreased [(3)H]-thymidine (in vitro) or BrdU (in vivo) incorporation, clonogenesis assays, cell cycle analysis and magnetic resonance imaging in living mice. Additionally, V3Nter switches off the β-catenin target gene expression signature in vivo. Moreover, experiments with β-catenin allele-targeted cells showed that the ΔS45 β-catenin allele hampers, but does not abrogate, inhibition of Wnt signaling by SFRP-1 or by the SFRP-like frizzled domain. Finally, neither SFRP-1 nor V3Nter affect β-catenin signaling in SW480 cells carrying nonfunctional Adenomatous polyposis coli. Thus, SFRP-1 and the SFRP-like molecule V3Nter can inhibit tumor growth of β-catenin-activated tumor cells in vivo.Oncogene advance online publication, 20 September 2010; doi:10.1038/onc.2010.432.
 INSERM, UMR991, Liver Metabolisms and Cancer, Rennes, France  Université de Rennes 1, Rennes, France.
This article was published in the following journal.
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20856206
- DOI: http://dx.doi.org/10.1038/onc.2010.432
Medical and Biotech [MESH] Definitions
Intercellular Signaling Peptides And Proteins
Regulatory proteins and peptides that are signaling molecules involved in the process of PARACRINE COMMUNICATION. They are generally considered factors that are expressed by one cell and are responded to by receptors on another nearby cell. They are distinguished from HORMONES in that their actions are local rather than distal.
Cell Adhesion Molecules, Neuronal
Surface ligands that mediate cell-to-cell adhesion and function in the assembly and interconnection of the vertebrate nervous system. These molecules promote cell adhesion via a homophilic mechanism. These are not to be confused with NEURAL CELL ADHESION MOLECULES, now known to be expressed in a variety of tissues and cell types in addition to nervous tissue.
Signaling proteins that are ligands for the EPH FAMILY RECEPTORS. They are membrane-bound proteins that are attached to the CELL MEMBRANE either through a GLYCOINOSITOL PHOSPHOLIPID MEMBRANE ANCHOR or through a transmembrane domain. Many of the ephrins are considered important intercellular signaling molecules that control morphogenic changes during embryogenesis.
Proto-oncogene Proteins C-fyn
Src-family kinases that associate with T-CELL ANTIGEN RECEPTOR and phosphorylate a wide variety of intracellular signaling molecules.
Intracellular Signaling Peptides And Proteins
Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.
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