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Human epithelial cell immortalization as a step in carcinogenesis.
Martha R Stampfer1, Paul Yaswen
1Lawrence Berkeley National Laboratory, Life Sciences Division, University of California, 1 Cyclotron Road, 70A1118, Berkeley, CA 94720-8174, USA. mrstampfer@lbl.gov <mrstampfer@lbl.gov>
Cancer Letters
|May 22, 2003
Summary
Human epithelial cells face two senescence barriers limiting growth. Overcoming the second barrier, dependent on telomeres and repressed telomerase, is crucial for cancer development and immortality.
Area of Science:
- Cellular senescence
- Cancer biology
- Molecular oncology
Background:
- Human epithelial cells possess intrinsic senescence barriers that limit proliferation.
- The retinoblastoma protein mediates the first barrier, often bypassed in cancers.
- A stringent, telomere-dependent second barrier arises from repressed telomerase activity.
Purpose of the Study:
- To define the errors required to overcome the telomere-dependent senescence barrier during in vivo carcinogenesis.
- To elucidate the role of telomerase reactivation in human carcinoma development.
Main Methods:
- Analysis of genetic and epigenetic alterations in human epithelial cells.
- Investigation of telomere length regulation and telomerase activity.
- In vivo carcinogenesis models.
Main Results:
- The second senescence barrier is extremely stringent and telomere-dependent.
- Ectopic human telomerase reverse transcriptase (hTERT) expression can relieve this barrier.
- Specific errors enabling immortality and telomerase reactivation are critical for carcinoma progression.
Conclusions:
- Attainment of cellular immortality through telomerase reactivation is essential for human carcinoma development.
- The specific genetic derangements enabling immortality may be rate-limiting steps in carcinogenesis.
- Understanding these barriers provides insights into cancer progression and potential therapeutic targets.