Introduction

Although the immortalization of human cells is a key step in oncogenic progression, the molecular mechanisms underlying this event are poorly understood. After reviewing the use of chemicals, physical agents, oncogenes and DNA tumour viruses as immortalizing agents, we consider the importance of negative regulators of cell growth (RB and p53), their inactivation, as well as genomic instability in the pathogenesis of cancer. Finally, a molecular model for human cell immortalization that integrates many of the above observations is presented along with supporting evidence.

What is Cell Immortalisation?

Immortalised Cell Line. Immortalized cell lines are either tumorous cells that do not stop dividing or cells that have been artificially manipulated to proliferate indefinitely and can, thus, be cultured over several generations.

Factors that Induce Cell Immortalisation

5. Chemicals
5. Physical techniques
5. Oncogenes
5. DNA tumour viruses
5. Anti-proliferative (tumour suppressor) genes
5. Genomic instability

Mechanism of Cell Immortalisation

The key to immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. The enzyme lengthens the caps, or telomeres, on the ends of chromosomes, which wear off during each cell division.

When the telomeres get too short, the ends stick to one another, wreaking havoc when the cell divides and in most cases killing the cell. The discovery of telomerase and its role in replenishing the caps on the ends of the chromosomes, made by Elizabeth Blackburn and Carol Greider at UC Berkeley and John Szostak at Harvard University in the 1980s, earned them a Nobel Prize in Physiology or Medicine in 2009.

Because telomeres get shorter as cells age, scientists theorized that cancer cells -- which never age -- become immortalized by turning on production of telomerase in cells that normally don't produce it, allowing these cells to keep their long telomeres indefinitely. An estimated 90 percent of all malignant tumours use telomerase to achieve immortality, and various proposed cancer therapies focus on turning down the production of telomerase in tumours.

The new research, which studied the immortalization process using genome-engineered cells in culture and also tracked skin cells as they progressed from a mole into a malignant melanoma, suggests that telomerase plays a more complex role in cancer.

Summary

It is postulated that two discrete stages (M1 and M2) need to be abrogated for human cells to progress beyond the normal senescence program and become immortal. We have cited evidence that in some instances loss of RB and p53 function may be two events required to overcome the M1 stage in human fibroblasts, although it has not been directly demonstrated that these genes are involved. Immortalization of human cells by SV40 large T-antigen, adenovirus E1A/EIB, and HPV16 E6/E7 may be attributed, in part, to bypassing the M1 stage by removal of the RB and p53 gene products. Genetic instability and other factors may also contribute to the inactivation of the M2 mechanism and the subsequent induction of immortalization.

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Journal of Molecular Oncology Research
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