Published in:
01-04-2010 | Original Paper
Loss of GDF-15 abolishes Sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer
Published in: Journal of Cancer Research and Clinical Oncology | Issue 4/2010
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Background
Growth-differentiation factor (GDF)-15, a member of the TGF-beta superfamily, is potently induced in the intestine following mechanical injury, genotoxic insult and following non-steroidal anti-inflammatory drugs (NSAIDs) exposure. GDF-15 expression correlates with apoptosis in intestinal cells and has been implicated in the pathogenesis of colorectal cancer formation and the anti-tumor effects of NSAIDs. We sought to determine the effect of loss of Gdf15 on animal tumor models of hereditary colon cancer and in the NSAID-mediated prevention of heritable colorectal cancer.
Methods
GDF-15 null (Gdf15
−/−) mice and mice with the genetic mutation found in hereditary poliposis coli, Apc
min/+
were bred. Gdf15
−/−
, Apc
min/+
and Gdf15
+/+
, Apc
min/+
mice were generated.
Results
In Gdf15
−/−
, Apc
min/+
mice, intestinal neoplasia formation rate and size were indistinguishable from that in Gdf15
+/+
, Apc
min/+
mice. Sulindac chemoprotection activity although potent in Gdf15
+/+
, Apc
min/+
mice was abolished in Gdf15
−/−
, Apc
min/+
mice.
Conclusions
These results demonstrate in a murine model that GDF-15 does not significantly regulate heritable in vivo intestinal carcinogenesis but does mediate sulindac chemoprevention in heritable colon cancer. These data suggest that the use of GDF-15 activated signaling pathways may allow improved chemoprevention and therapies for colorectal cancer.