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

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Abstract

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.

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Acknowledgments

We thank Alexis Sloan for help with the mice. Financial support was received from Sylvester Comprehensive Cancer Center, Dewitt Daughtry Family Department of Surgery, and the Papanicolaou Corps for Cancer Research (TAZ and LGK).

Conflict of interest statement

None of the authors has any personal or financial conflicts to declare.

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Authors and Affiliations

  1. Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Teresa A. Zimmers, Juan C. Gutierrez & Leonidas G. Koniaris

  2. Department of Cell Biology and Anatomy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 3550 SCCC (310T), 1475 NW 12th Ave, Miami, 33136, FL, USA

    Teresa A. Zimmers & Leonidas G. Koniaris

Authors
  1. Teresa A. Zimmers
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  2. Juan C. Gutierrez
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  3. Leonidas G. Koniaris
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Corresponding author

Correspondence to Teresa A. Zimmers.

Additional information

T. A. Zimmers and J. C. Gutierrez contributed equally to this report.

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Zimmers, T.A., Gutierrez, J.C. & Koniaris, L.G. Loss of GDF-15 abolishes Sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer. J Cancer Res Clin Oncol 136, 571–576 (2010). https://doi.org/10.1007/s00432-009-0691-4

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  • DOI: https://doi.org/10.1007/s00432-009-0691-4

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