Can Replicative Senescence Act To Promote Cancer

If cells that reach the Ml telomere length truly "senesce" in vivo, and then undergo the same kinds of changes in gene expression as they do in culture, this process could certainly have adverse effects on tissue function. In this regard one can pose a series of related questions: (i) Do cells undergo telomere shortening to the extent of reaching the Ml telomere length? (ii) If so, is the consequence of this the same as it is in culture, i.e. the generation of senescent cells, or do they suffer some other fate (e.g. crisis)? (iii) If they become senescent, do such cells accumulate in tissues, or are they eliminated by some part of either the acquired or innate immune system? (iv) If they do accumulate in tissues, do they exert a pro-carcinogenic effect because they secrete proteases and cytokines?

The most significant evidence for the occurrence of senescent cells in aging tissues is the occurrence of cells that stain for senescence-associated (3-galactosidase (SA-fS-gal) in tissues as a function of age. The presence of SA-(3-gal+ cells was first reported for human skin 32 and was subsequently shown in the rhesus monkey in retinal pigmented epithelium96 and in the epidermis 97. In these studies the number of SA-|3-gal+ cells increased as a function of donor age. These intriguing observations raise several questions. First, we do not know the mechanism by which such cells are formed; if their existence has consequences for tissue function, the mode by which they become senescent should be understood, so that appropriate interventions (both experimental and clinical) can be designed and tested. Second, whether such cells in vivo actually have the same range of changes in gene expression observed in replicative senescent cells in culture is also unknown. This is important, because it has been speculated that these changes may result in a pro-carcinogenic state in tissues that could aid the growth of pre-malignant cells and provide a permissive environment for tumor progression 98' 99 (Figure 3). It is conceivable that many properties of aging tissues, including an increased rate of neoplastic conversion, might result from the presence of relatively small numbers of replicative senescent cells.

Figure 3. Hypothetical scheme by which the presence of senescent cells in tissue during aging could exert a pro-neoplastic effect. In the young tissue, a cell with potentially oncogenic mutations ("initiated") is prevented from uncontrolled growth by neighboring cells. In the old tissue, senescent cells secrete enzymes and cytokines that enable the initiated cell to grow into a cancer. Reproduced with permission from Campisi, 2003.

Figure 3. Hypothetical scheme by which the presence of senescent cells in tissue during aging could exert a pro-neoplastic effect. In the young tissue, a cell with potentially oncogenic mutations ("initiated") is prevented from uncontrolled growth by neighboring cells. In the old tissue, senescent cells secrete enzymes and cytokines that enable the initiated cell to grow into a cancer. Reproduced with permission from Campisi, 2003.

Many more studies are needed in this area. First, the variety of tissues and the range of donor ages that have been surveyed so far is very small, and it is not possible yet to determine whether the occurrence of SA-cells is an inevitable part of normal aging or alternatively evidence of a pathological process. Studies in the prostate, liver, and vascular endothelium are suggestive of an accumulation of SA-(3-gal+ cells in disease states 100-102. Second, more studies are needed to show whether SA-(3-gal+ cells are generated by telomere shortening or by some other process. The suspicion that in some cases telomere shortening is not involved exists for retinal pigmented epithelial cells, because these cells are mostly postmitotic in adult life 103. These cells may have entered the senescent state as a form of stress-induced senescence as a result of exposure to oxidative damage.

Conversely, more studies are needed to show the fate of cells with shortening telomeres in tissues. One consequence of our lack of knowledge in this area is that SA-(3-gal+ staining cannot be used as an in situ assay for cells that have exhausted their replicative capacity in vivo by telomere shortening.

One final point is there has not yet been enough consideration given to alternate fates of cells that have undergone telomere shortening in vivo and whose telomeres have reached the Ml/senescent length. The possibility should be considered that their changes in gene expression might become so marked that they are no longer recognized as "self" and are eliminated by either acquired or innate immune functions, much as incipient cancer cells are eliminated by immune surveillance 104

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