The Function Evolutionarily Conserved Selective Value Of Replicative Senescence An Anticancer Mechanism

Because TERT appears to be re-expressed in the majority of human cancers 13, it is been hypothesized that the process by which TERT is repressed in most somatic cells is an anti-cancer mechanism. The best evidence that TERT repression is indeed an anti-cancer mechanism in human cells comes from data showing that the well-known oncoproteins Ras and SV40 T antigen cannot transform a normal human cell into a tumor cell unless they are also expressed together with TERT84. Presumably, the reason that TERT can co-operate with other oncogenes is that, during the process by which a normal cell and its descendants become fully malignant tumor cells, many cell divisions must take place and telomeres would become critically short, unless the cell activates telomerase or other mechanisms to prevent telomere shortening.

Thus the combination of initially short telomeres, suppression of TERT expression, and a checkpoint that triggers replicative senescence in response to short telomeres, together provide an anti-cancer mechanism. The existence of this anti-cancer mechanism in humans might contribute to the large difference in susceptibility to cancer (calculated on a per cell basis) between mice and humans. Suppose that mice and humans have the same risk of dying of cancer over their life spans (approximately true at least for some strains of mice 85. However, a human being is about 3,000 times heavier than a 25-gram mouse and lives about 30 times as long. Consider also that cells are about the same size in mice in humans and that cell turnover occurs at about same rate. All these assumptions may not be entirely correct but this does not substantially affect the basic validity of this argument. Then it is evident that human cells are approximately 90,000 times more resistant to tumorigenic conversion per unit of time than are mouse cells. Presumably, as part of the evolution of the life history of the human species, anti-cancer mechanisms evolved that were not present in short-lived ancestors. In this case the anti-cancer process may provide an example of antagonistic pleiotropy, the genetic event (repression of TERT) having beneficial effects in early life span and possibly negative effects in late life span86'87.

In mice, such anti-cancer strategies are unnecessary for their life history. Their small size and short life span means that they are not more likely than humans to die of cancer before being able to reproduce. Thus there has not been an evolutionary selective pressure to repress TERT expression in this species (and presumably in other similar small short-lived mammals, although this has not yet been well studied). Presumably there are similar arguments that can be made in terms of trade-offs between the advantages and disadvantages of long and short telomeres 74 Evidently, however, an organism that adopts TERT repression as an evolutionary anticancer strategy must also have short telomeres, or TERT repression becomes irrelevant to suppression of malignant transformation.

If suppression of TERT/short telomeres is a strategy that has evolved as an anti-cancer mechanism we are left with a puzzle. The senescent state appears to be a universal process, present in both human and mouse cells that is a reaction to certain kinds of DNA damage. The kinds of damage that cause cells to enter this state are very similar to those types of damage that cause other cells to enter apoptosis. From the point of view of the organism and the genome, making cells undergo apoptosis makes sense because the damaged cell and its progeny, carrying potentially damaged copies of the genome, are removed from the body. One may consider cells to be very cheap in terms of the overall economy of the body - millions of cells are born and die every day and there would seem to be no reason why cells should be preserved via the "replicative senescence" process, rather than killed off via apoptosis.

Therefore, one must ask the question, does replicative senescence occur in tissues in vivo? There is much evidence that telomere shortening occurs in tissues, but very little evidence directly addresses the question of whether telomere shortening causes cells to reach the same state in the body as it does in cell culture. In a recent review, Hanahan and Weinberg state: "The above-cited observations [on replicative senescence] might argue that senescence, much like apoptosis, reflects a protective mechanism that can be activated by shortened telomeres or conflicting growth signals that forces aberrant cells irreversibly into a G0-like state, thereby rendering them incapable of further proliferation. If so, circumvention of senescence in vivo may indeed represent an essential step in tumor progression that is required for the subsequent approach to and breaching of the crisis barrier. But we consider an alternative model equally plausible: senescence could be an artifact of cell culture that does not reflect a phenotype of cells within living tissues and does not represent an impediment to tumor progression in vivo. Resolution of this quandary will be critical to completely understand the acquisition of limitless replicative potential." [emphasis added] 88.

To state the problem in another way, the short telomere/TERT repression combination is generally accepted to be an anti-cancer mechanism, but we do not know if the anti-cancer effect is mediated through the replicative senescence/Ml cell cycle block, as it is observed in cell culture.

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