Abstract
BackgroundThe WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages.ResultsWe treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible.ConclusionWe show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.
Highlights
The wingless-type MMTV integration site family member (WNT) pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas
Deregulated WNT signalling contributes to the development and progression of many cancers, but very few WNT pathway antagonists have entered clinical trials. This might relate to the lack of efficacy of WNT inhibitors in cancer cells per se, or to difficulties in the specific targeting of cancer cells without interfering with the vital roles of WNT signalling in maintaining tissue homeostasis and adult stem cells
Small intestine tissue homeostasis is considered to depend on cycling, LGR5-expressing, WNT signallingdependent cells located in the crypt base, that are capable of generating all intestinal epithelial cell lineages [30]
Summary
The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. Colorectal tumours, in particular, often show dysregulated WNT/β-catenin signalling. Mutations in the adenomatous polyposis coli (APC) tumour suppressor gene or the gene encoding β-catenin (CTNNB1) result in colon adenomas [2, 3] and hypermethylation of SFRP1, a WNT antagonist, occurs frequently in colorectal cancer [4]. Various biotargets in the WNT/β-catenin signalling pathway have been used to develop pathway inhibitors (reviewed in [5]). Porcupine inhibitors that regulate the release of WNT morphogens [6] and tankyrases have been explored [7,8,9]. In the presence of WNT ligands, the β-catenin destruction complex does not form, β-catenin escapes ubiquitin–proteasome degradation and translocates to the nucleus to enable
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
