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Loss of p53 induces tumorigenesis in p21-deficient mesenchymal stem cells

Rene Rodriguez1, Ruth Rubio, Manuel Masip

  • 1Andalusian Stem Cell Bank (BACM)/University of Granada, 18100 Granada, Spain.

Neoplasia (New York, N.Y.)
|March 25, 2009
PubMed

Insights

Mesenchymal stem cells (MSCs) with p53 gene mutations lose cell cycle control, leading to tumor formation. These findings highlight MSCs

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Mesenchymal stem cells (MSCs) are increasingly implicated as cancer stem cells in various sarcomas.
  • The specific cellular and molecular mechanisms driving MSC transformation into cancer stem cells remain poorly understood.
  • p53 and p21 are key regulators of cell cycle progression and apoptosis, crucial for preventing tumorigenesis.

Purpose of the Study:

  • To investigate the role of p53 and p21 in the transformation of mesenchymal stem cells.
  • To determine how mutations in p53 and p21 affect MSCs' tumoral transformation properties in vitro and in vivo.

Main Methods:

  • Cultured mesenchymal stem cells from wild-type, p21(-/-)p53(+/+), and p21(-/-)p53(+/-) mice in vitro.
  • Analyzed MSCs for tumoral transformation properties after multiple in vitro and in vivo passages.
  • Assessed cell cycle regulators (p53, p21, p16), growth rate, karyotypic stability, senescence, and tumor formation.

Main Results:

  • Wild-type and p21(-/-)p53(+/+) MSCs did not exhibit tumoral transformation; wild-type cells senesced, while p21(-/-)p53(+/+) cells underwent apoptosis.
  • MSCs with a p53 heterozygous mutation (p21(-/-)p53(+/-)) lost p53 expression after prolonged in vitro culture.
  • Loss of p53 in p21(-/-)p53(+/-) MSCs led to increased growth rate, karyotypic instability, p16 loss, absent senescence, and fibrosarcoma formation in mice.

Conclusions:

  • MSCs are highly sensitive to genetic defects in cell cycle control pathways.
  • Mutations in p53 can drive MSC transformation, contributing to the development of mesodermic tumors like fibrosarcomas.
  • Understanding these mechanisms is crucial for targeting MSC-derived sarcomas.

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