Cancer stemness in Apc- vs. Apc/KRAS-driven intestinal tumorigenesis.
Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs) from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in Apc/KRAS tumours, they appear to be very rare (<10(-6)) in the Apc-mutant adenomas. In contrast, the Lin(-)CD24(hi)CD29(+) subpopulation of adenocarcinoma cells appear to be enriched in CSCs with increased levels of active β-catenin. Expression profiling analysis of the CSC-enriched subpopulation confirmed their enhanced Wnt activity and revealed additional differential expression of other signalling pathways, growth factor binding proteins, and extracellular matrix components. As expected, genes characteristic of the Paneth cell lineage (e.g. defensins) are co-expressed together with stem cell genes (e.g. Lgr5) within the CSC-enriched subpopulation. This is of interest as it may indicate a cancer stem cell niche role for tumor-derived Paneth-like cells, similar to their role in supporting Lgr5(+) stem cells in the normal intestinal crypt. Overall, our results indicate that oncogenic KRAS activation in Apc-driven tumours results in the expansion of the CSCs compartment by increasing ®-catenin intracellular stabilization.
Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
Mehrnaz
M
Ghazvini
Petra
P
Sonneveld
Andreas
A
Kremer
Patrick
P
Franken
Andrea
A
Sacchetti
Yaser
Y
Atlasi
Sabrina
S
Roth
Rosalie
R
Joosten
Ron
R
Smits
Riccardo
R
Fodde
D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D011905:Genes, ras; D016130:Immunophenotyping; D019012:Integrin beta1 / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D051176:beta Catenin / Q000378:metabolism
D051927:CD24 Antigen; D019012:Integrin beta1; D051176:beta Catenin