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Tumor suppressor p16INK4a determines sensitivity of human cells to transformation by cooperating cellular oncogenes

Sarah Drayton1, Janice Rowe, Rebecca Jones

  • 1Molecular Oncology Laboratory, Cancer Research UK London Research Institute, Lincolns Inn Fields, London WC2A 3PX, United Kingdom.

Cancer Cell
|October 31, 2003
PubMed

Insights

Human diploid fibroblasts lacking p16INK4a gained anchorage independence with telomerase and Ras or Myc. These cells formed tumors in mice, indicating further genetic alterations may be needed for full tumorigenesis.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cellular Biology

Background:

  • The Ink4a/Arf locus is crucial for senescence and tumor suppression.
  • It encodes two proteins, p16INK4a and Arf, with roles in cell cycle regulation and tumor prevention.

Purpose of the Study:

  • To investigate the role of p16INK4a deficiency in cellular transformation.
  • To determine if telomerase (hTERT) and oncogenes (Ras, Myc) can induce tumorigenesis in p16INK4a-deficient human diploid fibroblasts (HDFs).

Main Methods:

  • Human diploid fibroblasts (HDFs) were genetically modified to be deficient for p16INK4a.
  • Retroviral transduction was used to introduce genes for telomerase (hTERT) and oncogenes (Ras or Myc).
  • Anchorage independence assays, tumor formation in nude mice, and molecular/cytogenetic analyses were performed.

Main Results:

  • p16INK4a-deficient HDFs transduced with hTERT and Ras or Myc achieved anchorage independence.
  • Co-expression of Ras and Myc enabled tumor formation in nude mice, though at a low frequency.
  • Tumors retained functional p53, but some showed Arf downregulation, and all had clonal chromosomal alterations despite being near-diploid.

Conclusions:

  • Loss of p16INK4a, combined with telomerase and specific oncogenes, can initiate cellular transformation.
  • Tumorigenesis in this model likely requires additional genetic events beyond p16INK4a loss and oncogene activation.
  • Chromosomal instability may play a role in the progression of tumors arising from these modified cells.

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