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Figure 7.2 Morphological characteristics of cells with a senescent phenotype A tumor cell line containing cells with a typical senescent phenotype (right, arrowheads).

not easily ascertained, although cells with conspicuous morphologies that express SAP-GAL have been observed.

In cultured cells, replicative senescence can be more clearly defined and is elicited in two very different instances. The 'classic' mode of induction occurs after propagation of normal human cells over many passages. It sets in gradually. In fibroblasts, where the phenomenon was first described, it may occur after as many as 50-80 cell doublings. In cultured epithelial cells, it appears much earlier. It can be prevented by infection with certain DNA viruses, typically the SV40 papovavirus or its large T-antigen (^5.3). Thus, replicative senescence presents a limit to the lifespan of normal human somatic cells.

Replicative senescence can also be induced in a rapid mode, long before cells have exhausted their normal life-span, by inappropriate proliferation signals, specifically by overexpressed mutant RAS proteins. Unlike apoptosis and terminal differentiation, replicative senescence does not seem to be employed in the human body for tissue homeostasis. Rather, it appears to act as a fail-safe mechanism. Its only normal function may be setting a maximum to the human life-span (Box 7.1).

Evidently, cells in the germ-line must be exempt from replicative senescence. Moreover, it is plausible that tissue stem and/or early precursor cells must be subject to replicative senescence to a lower degree than more differentiated somatic cells, since during a human life-time in a continuously replicating tissue they will have to undergo many more than 100 divisions.

Replicative senescence is circumvented in many cancers. Cancer cells grown in culture or as xenografts in experimental animals can often be propagated for many more than 100 cell doublings and apparently indefinitely, without introducing Tantigen or its like. They are therefore considered 'immortalized'. It is, of course, difficult to ascertain immortalization as such in a human cancer tissue. It is easier in vitro, but not all human cancers can be grown in culture or as xenografts. Therefore, it is not certain whether all human cancers are really immortalized. Indefinite growth is not a necessary condition for a cancer to kill its host, because 50 cells doublings can theoretically produce more cells than an entire human body holds.

However, mechanisms that allow cancer cells in vitro to circumvent replicative senescence can be shown to be also active in many cancer tissues (^7.4). In other cases, tumor cells may evade replicative senescence by acquiring a kind of 'stem cell' character. This is evident in germ-cell cancers, e.g. in the testes or ovary. In addition, some cancers originating in somatic tissues may acquire (or maintain) properties of the respective tissue stem cell or early precursor, e.g. basal cell carcinoma of the skin (^12.3) and colon carcinoma (^13.2).

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