Senescence and Transformation.

Normal somatic cells that retain the capacity to proliferate in vitro do so usually only for a finite number of times. The progressive loss in proliferative capacity is called replicative senescence (see: Cell Aging In Vitro). In contrast with normal cells, cells derived from tumors usually have the ability to proliferate indefinitly in culture and for this reason are defined “immortal”. The scrupulous observation of how cells behave in culture allows us to better understand how they behave in vivo; so in the following discussion we will focus on cells in culture and we will try to clarify the terms “senescence”, “immortalization” and “transformation” especially in regards of how this terms apply to “normal” or “abnormal” cells (see Table 1). The proliferative capacity of stem cells In metazoans, following fertilization of the egg and initial cells divisions, the cells of the embryo differentiate into a germ cell lineage and a somatic cell lineage. The germ cells lineage is potentially immortal, in the sense that the complement of genes can be passed on indefinitely. It has been reported that mouse embryonic stem cells can be maintained for up to 250 cumulative doublings with no indication of crisis or transformation (1). In fact, the existing evidence suggests that, prior to differentiation, embryonic stem cells are immortal (2, 3) and probably so are also at least some adult stem cells (4). In contrast to germ cells and stem cells, all other somatic cells seems destined to encounter, sooner or later, replicative senescence. Undetectable karyotypic changes in some immortal cells A number of report involving various rodent, marsupial and fish cell culture indicate that these retain their proliferative capacity for what seems to be indefinite periods without any major alteration in karyotype. However, when many of these cell cultures are followed more carefully, they show a period of declining proliferative capacity (senescence) prior to the development of indefinite proliferative capacity (immortalization). This patter suggest that mutation of a subpopulation of cells has occurred. Certain culture derived from human lymphoid elements seem also to have an indefinite life span, although these may not truly be normal diploid cells and minor, or even undetectable, changes in karyotype that affect life span may be present. The best documented example of immortalized cells that display apparently normal karyotype but have undetectable or cryptic DNA changes causally related to transformation is found in chronic myelogenous leukemia (CML). A small subset of CML-affected individuals fail to exhibit the typical 9/22 translocation yet display the c-abl-ber fusion transcript and protein characteristic of the disease. Thus, molecular changes causally related to neoplastic transformations can occur in the absence of karyotypic changes. Immortalization: escaping senescence When primary cultures derived from normal tissue are subcultivated it may happens that an immortal culture with indefinite lif