Expression of Wnt genes in human colon cancers

Dimitriadis, Anna; Vincan, Elizabeth; Mohammed, Idris M; Roczo, Nandor; Phillips, Wayne A.; Baindur-Hudson, Swati

doi:10.1016/s0304-3835(01)00428-1

Cited by 37 publications

(26 citation statements)

References 27 publications

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“…In all seven colorectal cancer cell lines examined, we found expression of 3 or more of 11 members of the WNT family (Fig. 1a), a result consistent with previous studies in primary and cultured colorectal cancers [11][12][13] . Next, we asked whether SFRPs could downregulate WNT signaling in the colorectal cancer cell lines HCT116 and SW480, which harbor mutations in CTNNB1 and APC, respectively 2,3 .…”

supporting

confidence: 91%

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

et al. 2004

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Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers 1 . It occurs through mutations mainly of APC and less often of CTNNB1 (encoding β-catenin) 1-3 or AXIN2 (encoding axin-2, also known as conductin) 4 . These mutations allow ligandindependent WNT signaling that culminates in abnormal accumulation of free β-catenin in the nucleus 1-3 . We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzledrelated proteins (SFRPs) in colorectal cancer 5 . SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development 6-10 . Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.

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supporting

confidence: 91%

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

et al. 2004

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“…We found overexpression of the Wnt-1 protein in both cell lines examined (Figure 1a). This result suggests that the Wnt-1 protein level is consistent with its mRNA level studied previously in these colorectal cancer cells (Dimitriadis et al, 2001;Holcombe et al, 2002;Suzuki et al, 2004). In contrast, no noticeable Wnt-1 expression was detected in a normal colon cell line (Figure 1a).…”

supporting

confidence: 90%

Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations

et al. 2005

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Aberrant Wnt signaling, mainly through mutations of APC and in some cases of CTNNB1 or AXIN2, has been found in the majority of colorectal cancers. Recently, frequent promoter hypermethylation was identified to cause silencing of the secreted frizzled-related protein (sFRP) family in colorectal cancer. Restoration of sFRP in colorectal cancer cells attenuates Wnt signaling even in the presence of downstream mutations. Here we show that Wnt inhibitory factor-1 (WIF-1), a different secreted antagonist of Wnt signaling, is also silenced by promoter hypermethylation in colorectal cancer cells. Restoration of WIF-1 function, Wnt-1 siRNA, or a monoclonal antiWnt-1 antibody that we developed attenuates Wnt-1 signaling and induces significant apoptosis in these cells containing downstream mutations and expressing Wnt-1. In addition, this monoclonal anti-Wnt-1 antibody showed synergistic effects with docetaxel in treating these colorectal cancer cells and great efficacy in treating primary colorectal cancer cultures freshly prepared from patients. Therefore, our data support the hypothesis that constitutive Wnt signaling may be required to complement downstream mutations in the evolution of colorectal cancer. Furthermore, our results suggest that blockade of the Wnt signal may have a therapeutic role in the treatment of colorectal cancer.

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“…Enhanced autocrine Wnt signaling (Bafico et al, 2004) and epigenetic silencing of genes encoding endogenous extracellular Wnt inhibitors (Suzuki et al, 2004) provide a positive selection advantage to cells carrying b-catenin pathway mutations (Barker and Clevers, 2006;Polakis, 2007;MacDonald et al, 2009). In this setting, frizzled receptor activation and enhanced Wnt expression drive positive cancer cell selection (Vider et al, 1996; Smith et al, An SFRP-like frizzled motif blocks tumor growth E Lavergne et al 1999; Dimitriadis et al, 2001;Holcombe et al, 2002;Ueno et al, 2008). Consequently, extracellular Wnt inhibitors such as SFRPs (Taketo, 2004), Wnt inhibitory factor-1 (Hu et al, 2009) or anti-Wnt1 antibodies (He et al, 2005) block tumor cell growth in cells carrying mutant b-catenin.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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

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Expression of Wnt genes in human colon cancers

Cited by 37 publications

References 27 publications

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations

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

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