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Related Experiment Videos

Stabilized beta-catenin immortalizes colonic epithelial cells.

R A Wagenaar1, H C Crawford, L M Matrisian

  • 1Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

Cancer Research
|March 31, 2001
PubMed
Summary

Stabilized beta-catenin (beta-cat) protein immortalizes and transforms colon cancer precursor cells. This finding clarifies the oncogenic role of beta-catenin in colorectal cancer development.

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Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis.

Neoplasia (New York, N.Y.)·2002

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Colonic neoplasias frequently harbor mutations in adenomatous polyposis coli (APC) or beta-catenin (beta-cat) genes, leading to elevated beta-cat levels.
  • The precise in vivo and in vitro oncogenic activity of beta-catenin remains incompletely understood, with conflicting experimental results.

Purpose of the Study:

  • To investigate the hypothesis that beta-catenin can immortalize and transform epithelial cells that are precursors to colon cancer.
  • To elucidate the role of stabilized beta-catenin in cellular senescence and apoptosis in the context of colorectal cancer development.

Main Methods:

  • Utilized conditionally immortalized murine colonic epithelial cells (IMCE) with a mutant ApcMin allele.
  • Stably expressed a truncated beta-catenin (deltaN89) in IMCE cells and assessed immortalization by sustained growth and escape from senescence.

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  • Evaluated transformation through assays for growth in low serum, anchorage-independent growth, and tumor formation in nude mice.
  • Measured protein levels of p19 and p53 to understand their role in beta-catenin-mediated effects.

    • Main Results:

    • Expression of deltaN89 beta-catenin conferred immortalization to IMCE cells, evidenced by sustained proliferation and resistance to senescence.
    • Beta-catenin expression blocked apoptosis in IMCE cells under non-permissive conditions.
    • IMCE cells expressing beta-catenin exhibited reduced p19 and p53 protein levels, suggesting mediation of senescence and apoptosis.
    • Transformed IMCE beta-catenin cells demonstrated anchorage-independent growth and formed tumors in vivo.
    • Successful generation of stable beta-catenin-expressing cells was only achieved in a mutant Apc background.

    Conclusions:

    • Demonstrated for the first time the immortalizing capacity of stabilized beta-catenin in a relevant cellular model.
    • Extended the understanding of mutated beta-catenin's transforming potential to colorectal cancer precursor cells.
    • Highlighted the potential role of p19 and p53 in mediating beta-catenin's effects on cellular fate.