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

Teresa Zimmers, Juan C. Gutierrez, Leonidas Koniaris

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)571-576
Number of pages6
JournalJournal of Cancer Research and Clinical Oncology
Volume136
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

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Growth Differentiation Factor 15
Sulindac
Intestinal Neoplasms
Chemoprevention
Colorectal Neoplasms
Anti-Inflammatory Agents
Colonic Neoplasms
Pharmaceutical Preparations
Neoplasms
Transforming Growth Factor beta
Intestines
Carcinogenesis
Animal Models
Apoptosis
Mutation

Keywords

  • Colon cancer
  • COX-2
  • Cytokine
  • NSAID
  • TGF-beta

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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title = "Loss of GDF-15 abolishes Sulindac chemoprevention in the Apc Min/+ mouse model of intestinal cancer",
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.",
keywords = "Colon cancer, COX-2, Cytokine, NSAID, TGF-beta",
author = "Teresa Zimmers and Gutierrez, {Juan C.} and Leonidas Koniaris",
year = "2010",
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pages = "571--576",
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TY - JOUR

T1 - Loss of GDF-15 abolishes Sulindac chemoprevention in the Apc Min/+ mouse model of intestinal cancer

AU - Zimmers, Teresa

AU - Gutierrez, Juan C.

AU - Koniaris, Leonidas

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

KW - Colon cancer

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