Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

Abstract

Constitutive activation of Wnt/b-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 b-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 DS45 activating mutation in one of the alleles of b-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced b-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

Expression of EpCAM and Wnt/ β-catenin in human colon cancer

“…The results of this study suggest that EpCAM can be considered as a new therapeutic target in the adjuvant chemotherapy for colon cancers. In Europe, anti-EpCAM monoclonal antibody drugs have been recently used in patients with malignant ascites (Lavergne et al, 2011). In this study, the result of cell culture shows that EpCAM-targeted therapy may also have significance for the treatment of colon cancers, and it is therefore worthwhile to carry out further basic and clinical research and drug development towards this goal.…”

Secreted frizzled related proteins: Implications in cancers

“…These papers also summarized the antagonizing effects of SFRP molecules on Wnt-induced increases in free β-catenin levels and morphological alterations. Also, SFRPs and SFRP-like molecules affected cell cycle progression and decreased tumour cell proliferation [26]. SFRP proteins have thus emerged as potential Wnt antagonists and a new class of tumour suppressors ( Figure 2).…”

Targeting Leukemia Stem Cells: Which Pathways Drive Self-Renewal Activity in T-Cell Acute Lymphoblastic Leukemia?

“…Negative physiologic regulators of Wnt signalling, such as the secreted Frizzled-related proteins and the Dickkopf-related protein 1, have been used as natural inhibitors of the Wnt pathway in cancer [68][69][70] . However, since about 2005, highthroughput screening of libraries containing small chemical compounds on cells transduced with Wnt reporters have identified various synthetic inhibitors of Wnt signalling-among them, the molecules X AV939 and pyrvinium.…”