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Mutation of TGFβ-RII eliminates NSAID cancer chemoprevention

Juana Martín-López1, Pierluigi Gasparini1, Kevin Coombes2

  • 1Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Oncotarget
|March 22, 2018
PubMed

Insights

Non-steroidal anti-inflammatory drugs (NSAIDs) suppress tumors in Lynch syndrome models. However, blocking TGFβ signaling completely eliminates this chemoprevention effect, revealing a key mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) show chemoprevention effects against sporadic and hereditary cancers, including Lynch syndrome (LS/HNPCC).
  • The precise mechanism underlying NSAID-mediated tumor suppression remains unclear.
  • Defects in mismatch repair (MMR) genes MSH2 and MLH1 are primary causes of LS/HNPCC.

Purpose of the Study:

  • To investigate the role of TGFβ signaling in NSAID-dependent chemoprevention of intestinal tumors in a mouse model of Lynch syndrome.
  • To elucidate the genetic pathways involved in NSAID tumor suppression.

Main Methods:

  • Utilized a villin-Cre-Msh2 (VpC-Msh2) mouse model for LS/HNPCC intestinal tumorigenesis.
  • Introduced a TGFβ receptor type-II (Tgfβ-RII) mutation into the VpC-Msh2 model, creating the villin-Cre-RII mouse.
  • Assessed the impact of aspirin (ASA) treatment on tumor suppression in both mouse models.

Main Results:

  • Aspirin (ASA) significantly suppressed intestinal tumorigenesis in the VpC-Msh2 mouse model, mirroring human chemoprevention.
  • The presence of the Tgfβ-RII mutation in the villin-Cre-RII mouse completely abolished the tumor-suppressive effects of ASA.
  • This indicates a critical role for TGFβ signaling in NSAID-mediated anti-neoplastic activity.

Conclusions:

  • TGFβ signaling and/or its effectors are essential components of NSAID-dependent anti-neoplastic processes.
  • These findings offer new insights into the mechanisms of NSAID chemoprevention and resistance.
  • The study highlights potential therapeutic targets for enhancing cancer chemoprevention strategies.
Keywords:
COX-independentcardioprotectioncolon cancermismatch repairnaproxen

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