Markedly eroded telomeres are recognized by the DNA repair machinery as double-stranded DNA breaks, leading to cell cycle arrest and senescence, mediated by TP53 and RB. In cells in which TP53 or RB mutations are disabled by mutations, the nonhomologous end-joining pathway is activated in a last-ditch effort to save the cell, joining the shortened ends of two chromosomes.
Such an inappropriately activated repair system results in dicentric chromosomes that are pulled apart at anaphase, resulting in new double-stranded DNA breaks. The resulting genomic instability from the repeated bridge– fusion–breakage cycles eventually produces mitotic catastrophe, characterized by massive apoptosis.
It follows that for tumors to acquire the ability to grow indefinitely, loss of growth restraints is not enough; both cellular senescence and mitotic catastrophe must also be avoided (
Fig. 6.26 ). If during crisis a cell manages to reactivate telomerase, the bridge–fusion–breakage cycles cease, and the cell is able to avoid death. However, during this period of genomic instability that precedes telomerase activation, numerous mutations could accumulate, helping the cell march toward malignancy. Telomerase, active in normal stem cells, is absent from or present at very low levels in most somatic cells. By contrast, telomere maintenance is seen in virtually all types of cancers. In 85% to 95% of cancers, this is due to upregulation of the enzyme telomerase. A few tumors use other mechanisms, termed alternative lengthening of telomeres, which depend on DNA recombination.
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Fig. 6.26 Escapeofcellsfromreplicativesenescenceandmitoticcatastrophecausedbytelomereshortening.
Of interest, in a study of the progression from colonic adenoma to colonic adenocarcinoma, early lesions had a high degree of genomic instability with low telomerase expression, whereas malignant lesions had complex karyotypes with high levels of telomerase activity, consistent with a model of telomere-driven tumorigenesis in human cancer. Thus, it appears that unregulated proliferation in incipient tumors leads to telomere shortening, followed by chromosomal instability and the accumulation of mutations. If telomerase is then reactivated in these cells, telomeres are extended and these mutations become fixed, contributing to tumor growth.
•Innormalcells,whichlackexpressionoftelomerase,theshortenedtelomeresgeneratedbycelldivisioneventuallyactivatecellcyclecheckpoints,leadingtosenescenceandplacingalimitonthenumberofdivisionsacellmayundergo.
Incellsthathavedisabledcheckpoints,DNArepairpathwaysareinappropriatelyactivatedbyshortenedtelomeres,leadingtomassivechromosomalinstabilityandmitoticcrisis.
Tumorcellsreactivatetelomerase,thusstavingoffmitoticcatastropheandachievingimmortality.