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Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells.

ABSTRACT: Aberrant regulation of the Wnt/?-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or ?-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or ?-catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind ?-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or ?-catenin depend on Wnt ligands and their secretion for a sufficient level of ?-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls.

SUBMITTER: Voloshanenko O

PROVIDER: S-EPMC3826636 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells.

Voloshanenko Oksana O Erdmann Gerrit G Dubash Taronish D TD Augustin Iris I Metzig Marie M Moffa Giusi G Hundsrucker Christian C Kerr Grainne G Sandmann Thomas T Anchang Benedikt B Demir Kubilay K Boehm Christina C Leible Svenja S Ball Claudia R CR Glimm Hanno H Spang Rainer R Boutros Michael M

Nature communications 20130101

Aberrant regulation of the Wnt/β-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or β-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in ...[more]

PMID: 24162018

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Project description:Ulcerative colitis (UC) increases the risk of colorectal cancer (CRC), but the mechanisms involved in colitis-to-cancer transition (CCT) are not well understood. CCT may involve a inflammation-dysplasia-carcinoma progression sequence compared with the better characterized adenoma-carcinoma progression sequence associated with sporadic CRC. One common thread may be activating mutations in components of the Wnt/?-catenin signaling pathway, which occur commonly as early events in sporadic CRC. To examine this hypothesis, we evaluated possible associations between Wnt/?-catenin signaling and CCT based on the cancer stem cell (CSC) model. Wnt/?-catenin immunostaining indicated that UC patients have a level of Wnt-pathway-active cells that is intermediate between normal colon and CRC. These UC cells exhibiting activation of the Wnt pathway constituted a major subpopulation (52% + 7.21) of the colonic epithelial cells positive for aldehyde dehydrogenase (ALDH), a putative marker of precursor colon CSC (pCCSC). We further fractionated this subpopulation of pCCSC using a Wnt pathway reporter assay. Over successive passages, pCCSCs with the highest Wnt activity exhibited higher clonogenic and tumorigenic potential than pCCSCs with the lowest Wnt activity, thereby establishing the key role of Wnt activity in driving CSC-like properties in these cells. Notably, 5/20 single cell injections of high-Wnt pCCSC resulted in tumor formation, suggesting a correlation with CCT. Attenuation of Wnt/?-catenin in high-Wnt pCCSC by shRNA-mediated downregulation or pharmacological inhibition significantly reduced tumor growth rates. Overall, the results of our study indicates (i) that early activation of Wnt/?-catenin signaling is critical for CCT and (ii) that high levels of Wnt/?-catenin signaling can further demarcate high-ALDH tumor-initiating cells in the nondysplastic epithelium of UC patients. As such, our findings offer plausible diagnostic markers and therapeutic target in the Wnt signaling pathway for early intervention in CCT.

Dataset Information

Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells.

Publications

Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells.

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