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The involvement of a Nanog, Klf4 and c-Myc transcriptional circuitry in the intertwining between neoplastic

Ilaria Marzi1, Maria Grazia Cipolleschi, Massimo D'Amico

  • 1Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy.

Cell Cycle (Georgetown, Tex.)
|January 5, 2013
PubMed

Insights

Chemical carcinogens can induce tumors by combining cancer progression with cellular reprogramming. This study reveals that reprogramming factors in tumors are reversible, offering new insights into cancer development and potential therapeutic strategies.

Area of Science:

  • Oncology
  • Developmental Biology
  • Cancer Research

Background:

  • Neoplastic progression involves genetic mutations leading to dedifferentiated cells.
  • Somatic cell reprogramming to pluripotent stem cells is achievable via transcription factor overexpression.
  • The role of reprogramming in tumorigenesis and its reversibility remain key questions.

Purpose of the Study:

  • To investigate the interplay between neoplastic progression and cellular reprogramming in chemically induced tumors.
  • To determine if epigenetic changes driving reprogramming in tumors are reversible.
  • To explore the potential of reprogramming for cancer therapy.

Main Methods:

  • Utilized the Yoshida AH130 hepatoma ascites tumor model and other neoplasms, including human melanoma.
  • Induced hepatoma using the carcinogen o-aminoazotoluene, which targets the p53 protein.
  • Analyzed tumor cells for CD133 expression and embryonic transcription factors (Nanog, Klf4, c-Myc) under varying oxygen levels.
  • Cultured tumor cells in aerobic conditions to observe differentiation potential.

Main Results:

  • The carcinogen o-aminoazotoluene induced genomic instability, promoting both neoplastic progression and reprogramming in hepatoma.
  • Tumors contained CD133(+) cells and showed pO(2)-dependent expression of Nanog, Klf4, and c-Myc.
  • A subpopulation of tumor cells expressing these factors could differentiate into non-tumorigenic fibromuscular, neuronal, and glial cells in aerobic culture.
  • Reprogramming occurred stepwise via a transcriptional, oxygen-dependent circuit involving Nanog, Klf4, and c-Myc.

Conclusions:

  • Chemically induced tumors result from the interaction of neoplastic progression and cellular reprogramming.
  • The reprogramming process in tumors is reversible and can lead to differentiation of non-tumorigenic cells.
  • Understanding this reprogramming circuitry offers potential avenues for novel cancer therapies targeting tumor plasticity.
Keywords:
cancer metabolismembryonic transcription factorsneoplastic progressionp53 lackpO2 and cell cycletumor reprogramming

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