Loss of GDF-15 abolishes sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer.
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.
Zimmers
Teresa A
TA
Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. tzimmers@med.miami.edu
Gutierrez
Juan C
JC
Koniaris
Leonidas G
LG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D004195:Disease Models, Animal; D017491:Genes, APC; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D013467:Sulindac / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D055436:Growth Differentiation Factor 15; D013467:Sulindac