ABSTRACT
Aspirin reduces the incidence and mortality of colorectal cancer (CRC). Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.
Footnotes
Author names in bold designate shared co-first authorship
Abbreviations
- APC
- Adenomatous polyposis coli
- CRC
- Colorectal cancer
- CSC
- Cancer stem cells
- DKK-1
- Dickkopf-1
- EMT
- Epithelial-Mesenchymal transition
- F-actin
- Filamentous actin
- FAP
- Familial adenomatous polyposis
- GSK-3B
- Glycogen synthase kinase 3B
- LEF
- Lymphoid enhancer factor
- Lgr5
- Low-density lipoprotein receptor-related protein 6
- LRP6
- Leucine-rich repeat-containing G-protein coupled receptor 5
- mTOR
- Mechanistic target of rapamycin
- NSAID
- Non-steroidal anti-inflammatory drug
- PBS
- Phosphate buffered saline
- PDVF
- Polyvinylidene difluoride
- Rac1
- Ras-related C3 botulinum toxin substrate 1
- RhoA
- Ras homolog gene family, member A
- RNA
- Ribonucleic acid
- ROCK1
- Rho-associated protein kinase 1
- ROCK2
- Rho-associated protein kinase 2
- SDS-PAGE
- Sodium dodecyl sulphate polyacrylamide gel electrophoresis
- TCF
- T-cell factor
- TGF-B
- Transforming growth factor beta
- TROY
- Tumour necrosis factor receptor superfamily member 19
- ZO-1
- Zona-occludens 1