Caught up in a Wnt storm: Wnt signaling in cancer

Giles, Rachel; Es, Johan H. van; Clevers, Hans

doi:10.1016/s0304-419x(03)00005-2

Cited by 1,065 publications

(1,328 citation statements)

References 293 publications

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“…The other type is initiated by lack of both wild-type Apc alleles through loss of heterozygosity (LOH) in the Apc D716 (Apc þ /D716 ) mutant mouse (Oshima et al, 1995). In the b-catenin mutant mice expressing Cre in the small intestine, b-catenin protein is stabilized by Cre-mediated deletion of the exon 3 that encodes amino acids, including all four phosphorylation targets for ubiquitylation (Giles et al, 2003). On the other hand, b-catenin protein in the Apc D716 mutant mouse is stabilized because glycogen synthase kinase 3b-mediated phosphorylation of b-catenin is suppressed due to the absence of intact APC protein that provides the scaffold for these proteins (Giles et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…In the b-catenin mutant mice expressing Cre in the small intestine, b-catenin protein is stabilized by Cre-mediated deletion of the exon 3 that encodes amino acids, including all four phosphorylation targets for ubiquitylation (Giles et al, 2003). On the other hand, b-catenin protein in the Apc D716 mutant mouse is stabilized because glycogen synthase kinase 3b-mediated phosphorylation of b-catenin is suppressed due to the absence of intact APC protein that provides the scaffold for these proteins (Giles et al, 2003). As anticipated, b-catenin was localized in the adenoma epithelial nuclei, whereas it was found mostly in the cytoplasmic membrane in the normal (non-polyp) epithelium in the b-catenin mutant mouse ( Figure 1a; Harada et al, 1999) as well as in the Apc D716 mouse (Harada et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

“…High ABI in 'intestinal-type' human gastric cancer tissues with Wnt signal activation As most colorectal cancer tissues show activation of b-catenin/TCF transcription (Giles et al, 2003), we then examined human gastric cancer samples, with and without nuclear b-catenin staining, respectively, and determined their ABI. Histologically, they were classified as 'intestinal type' associated with intestinal metaplasia (Figure 4a-d), or 'diffuse type' with undifferentiated morphology (Ushijima and Sasako, 2004).…”

Section: Es Cells With High Abi Produce New Chromosomal Aberrationsmentioning

confidence: 99%

“…Activation of the canonical Wnt signal pathway induces transcription of a new set of genes through the b-catenin/T-cell factor (TCF) complex, which regulates cell proliferation and differentiation (Kielman et al, 2002;Giles et al, 2003). In most colon cancer cells, the pathway is activated through mutations in the adenomatous polyposis coli (APC), AXIN1 or b-catenin (CTNNB1) gene.…”

Section: Introductionmentioning

confidence: 99%

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Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Aoki

Sugai

et al. 2006

Oncogene

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Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate b-catenin/ T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or b-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signalactivated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear b-catenin, ABI was significantly higher than in those without. These results collectively indicate that b-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Es Cells With High Abi Produce New Chromosomal Aberrationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Aoki

Sugai

et al. 2006

Oncogene

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“…[21][22][23] The accumulation of cytoplasmic b-catenin and its translocation to the nucleus has been associated with epithelial cell migration and invasion in various physiological and pathological processes including tumour progression. 21,[23][24][25][26] Several b-catenin/TCF target genes have now been identified. They pertain to various families of proteins including matrix metalloproteases, cytoskeletal proteins or angiogenic cytokines and chemokines (IL-8, MMP-7, MMP-14, CD44, cyclin D1, c-myc, claudin-1, vimentin, MMP26, VEGF.…”

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confidence: 99%

Transactivation of MCP‐1/CCL2 by β‐catenin/TCF‐4 in human breast cancer cells

Mestdagt

Polette

Butticè

et al. 2005

Intl Journal of Cancer

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The loss of E-cadherin expression and the translocation of b-catenin to the nucleus are frequently associated with the metastatic conversion of epithelial cells. In the nucleus, b-catenin binds to the TCF/LEF-1 (T-cell factor/ lymphoid enhancer factor) transcription factor family resulting in the activation of several genes, some of them having important implications in tumour progression. In our study, we investigated the potential regulation of monocyte chemotactic protein-1 (MCP-1/CCL2) expression by the b-catenin/TCF pathway. This CC-chemokine has been implicated in tumour progression events such as angiogenesis or tumour associated macrophage (TAM) infiltration. We thus demonstrated that MCP-1 expression correlates with the reorganization of the E-cadherin/b-catenin complexes. Indeed, MCP-1 was expressed by invasive breast cancer cells (MDA-MB-231, BT549 and Hs578T), which do not express E-cadherin but was not produced by noninvasive breast cancer cell lines (MCF7 and T47D) expressing high level of E-cadherin. In addition, the MCP-1 promoter was activated in BT549 breast cancer cells transfected with b-catenin and TCF-4 cDNAs. The MCP-1 mRNA level was similarly upregulated. Moreover, we showed that MCP-1 mRNA was downregulated after transfection with a siRNA against b-catenin in both BT549 and Hs578T cells. Our results therefore identify MCP-1 as a target of the b-catenin/TCF/LEF pathway in breast tumour cells, a regulation which could play a key role in breast tumour progression. ' 2005 Wiley-Liss, Inc.Key words: MCP-1; b-catenin; breast cancer Chemokines constitute a superfamily of proinflammatory cytokines that are implicated in tumour progression, modulating not only host tumour-specific immunological response but also angiogenesis or tumour cell invasion and proliferation. 1-3 Monocyte chemotactic protein-1 (MCP-1) or CCL2 is a CC-chemokine that specifically attracts monocytes and memory T cells. It has been particularly implicated in processes characterized by mononuclear cell infiltration including breast cancer. 4,5 In some models, MCP-1 has been shown to display an antitumoral effect. 6,7 Nevertheless, a large number of studies demonstrate that MCP-1 facilitates tumour progression through its ability to recruit stromal cells including tumour associated macrophages (TAMs) and endothelial cells. 7-10 A pro-angiogenic role of MCP-1 has been demonstrated in many systems, facilitating tumour growth and dissemination. 8,9,11,12 Moreover, a direct effect of MCP-1 on tumour cell migration in vitro has also been described. 13 Recently, Lebrecht et al. 14 have correlated an increased MCP-1 serum level with an advanced breast tumour stage and the presence of lymph node metastasis. In the same way, Amann et al. 15 reported a significant association between MCP-1 urinary levels and tumour stage and grade. They suggested a use of its urinary level as prognosis marker in bladder cancer. The correlation between MCP-1 expression and a poor prognosis was also demonstrated for the squamous cell carcinoma of the oeso...

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