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Restoring TGFbeta function in microsatellite unstable (MSI-H) colorectal cancer reduces tumourigenicity but increases

Janindra Warusavitarne1, Fiona McDougall, Keshani de Silva

  • 1Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St. Leonards, NSW, 2065, Australia. j.warusavitarne@garvan.org.au

International Journal of Colorectal Disease
|November 6, 2008
PubMed
Abstract

Insights

Restoring the transforming growth factor beta receptor II (TGFbetaRII) gene in microsatellite unstable (MSI-H) colon cancer cells significantly increased invasion and metastasis. This finding explains the low metastatic rate in MSI-H colon cancers and highlights TGFbeta signaling

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • Transforming growth factor beta (TGFbeta) is a key regulator of cell growth with implications in metastasis.
  • Microsatellite unstable (MSI-H) colon cancers, often characterized by mutations in the TGFbeta receptor II (TGFbetaRII) gene, exhibit a low metastatic rate.
  • This unique characteristic makes MSI-H colon cancer a valuable model for studying TGFbeta's role in metastasis.

Purpose of the Study:

  • To investigate the impact of restoring wild-type TGFbetaRII on invasion and metastasis in an MSI-H colorectal cancer cell line.
  • To elucidate the role of TGFbeta signaling pathway in the metastatic potential of MSI-H colon cancer.

Main Methods:

  • The KM12C MSI-H colorectal carcinoma cell line, possessing a mutated TGFbetaRII gene, was transfected with the wild-type TGFbetaRII gene.
  • Invasion and metastasis assays were performed using the modified cell line.
  • A mouse metastatic model was employed to assess liver metastasis following inoculation with transfected and control cells.

Main Results:

  • Restoration of the wild-type TGFbetaRII gene significantly increased both invasion and metastasis in the KM12C cell line.
  • In a mouse model, liver metastases were significantly higher in mice inoculated with cells expressing wild-type TGFbetaRII (42%) compared to control cells (15%; p = 0.0379).
  • Interestingly, primary tumor size was reduced in the transfected group despite increased metastasis.

Conclusions:

  • This study identifies a crucial mechanism contributing to the low metastatic rate observed in MSI-H colon cancers.
  • The findings underscore the critical role of TGFbeta signaling in the process of cancer metastasis.
  • This research is the first to demonstrate that restoring TGFbeta signaling in a low-metastatic MSI-H colon cancer cell line with TGFbetaRII mutations can enhance metastatic potential.

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