RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis.

Gut 2017 06 10;66(6):1095-1105. Epub 2016 Aug 10.

Department of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objective: The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli ( or mutations. However, a subset of human colon tumours harbour, mutually exclusive with and mutations, gene fusions in or leading to enhanced expression of these R-spondin genes. This suggested that activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in -fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel.

Design: We generated a conditional transgenic mouse model in which the transgene is expressed upon Cre activity. Cre is provided by cross-breeding with -GFP-Cre mice.

Results: Upon in vivo expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5 stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4 cells, thus promoting both intestinal stem cell and niche compartments. Wnt/β-catenin signalling was modestly increased upon expression and mutant synergised with in hyperplastic growth.

Conclusions: We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring fusions.

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2016-311606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532462PMC
June 2017

Publication Analysis

Top Keywords

niche compartments
12
driver intestinal
12
intestinal cancer
12
stem cell
12
cell niche
12
compartments drives
8
wnt/β-catenin signalling
8
rspo3
8
intestinal stem
8
colorectal cancer
8
intestinal
6
cancer
5
cre activity
4
cre provided
4
expressed cre
4
-gfp-cre miceresults
4
activity cre
4
provided cross-breeding
4
cross-breeding -gfp-cre
4
miceresults vivo
4

Similar Publications