Loss of GDF-15 abolishes Sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer


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. 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. 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. 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.

DOI: 10.1007/s00432-009-0691-4

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@article{Zimmers2009LossOG, title={Loss of GDF-15 abolishes Sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer}, author={Teresa A. Zimmers and Juan C. Garc{\'i}a Gutierrez and Leonidas G. Koniaris}, journal={Journal of Cancer Research and Clinical Oncology}, year={2009}, volume={136}, pages={571-576} }