Advancing age has been described as the most potent of all carcinogens.16 In humans, the incidence of cancer rises exponentially in the final decades of life, culminating in a lifetime risk of 1 in 2 for men and 1 in 3 for women.17 This dramatic escalation in the incidence of cancer among the aged is largely due to epithelial carcinomas that develop between ages 40 and 80.
Until recently, the most common explanation for the increased incidence of cancer among older people has been the accumulation of somatic mutations due to cumulative exposure to both endogenous and exogenous DNA damaging agents18,19 and failure to repair mismatches occurring during DNA replication.20 In Chapter 1 it was shown that failure to repair mismatches occurring during DNA replication represents an early event in carcinogenesis21,22 and configures the so-called "mutator phenotype," in which many genes carry mutations because of uncorrected errors in DNA replication.23 The inability of the cell to correct mismatches that "normally" occur during DNA replication leads to an abnormal accumulation of "spontaneous mutations" and a consequent increase in DNA damage and genome instability.
The demonstration of the "mutator pheno-type"24,25 resolved one of the most important issues linked to the theory of the accumulation of somatic mutation with age: the insufficiency of the observed spontaneous mutation rate to account for the extensive tumor-associated genomic changes. In fact, in the new scenario of the "mutator phenotype," the age-dependent increase in the incidence of cancer stems from mutations affecting the genes governing the correction of mismatches occurring during DNA replication and the genome's stability, with a consequent accelerated pace of mutation overall.
Within this fundamental issue concerning the age-related increase in the incidence of cancer, it must be noted that several groups have provided experimental evidence in support of the suggestion that DNA repair activity declines with age. We showed in Chap part one: current concepts of oncogenesis ter 1 that microsatellite instability (MSI) represents the "signature" associated with DNA repair defects,26 and can be found in several cancer types. However, MSI is not always associated with cancer in the aged. Therefore, although the failing DNA mismatch repair system surely accounts for a consistent explanation of many age-associated cancer types, it does not explain them all. Other mechanisms must be at work, including those described in Chapter 1 as "epigenetic" which entail both DNA methylation and modifications of chromatin structure. Age-progressive CpG island methylation (and consequent gene silencing) has been observed to take place in subsets of cells residing in normal tissues. One example may be represented by the age-progressive methylation of the genes for estrogen receptors, with consequent silencing of these genes and increased cancer incidence in older women.
It has been outlined that the root source of genomic instability, which, in turn, represents the hallmark of nearly all solid tumors and adult-onset leukemia, is represented by the imbalance between DNA damage and repair, with damage prevailing because of either an increased rate of mutation or a decreased ability of the system to repair the damage incurred. Also, epi-genetic events, such as gene methylation or histone acetylation, play a fundamental role in the process of genomic destabilization leading to cancer. Inherent in the concept of damage accumulation is the concept of time; it seems logical to assume that to allow for damage to accumulate and produce the irreversible alterations typical of cancer, a close relationship between increased age and cancer incidence must exist at the systemic level.
When aging and its relationship to cancer are considered at the cellular level, new and very interesting aspects are discovered. Investigations on the physiology of cell senescence and proliferative aging have led to the discovery of the telomere-telomerase system, which seems to be of extreme relevance to both aging and cancer. It is known that with each cell division, the genetic code is transferred as chromosomes are replicated and distributed into daughter cells. To ensure that the transfer is carried out in an accurate and efficient manner, different cellular mechanisms are in place, including the semiconservative replication of DNA and cell senescence.
The semiconservative replication of DNA is the process of replicating the original DNA in such a way that the finished products are two double DNA strands, each with one original and one new strand, to be distributed to the daughter cells. The mechanism of DNA replication in linear chromosomes is different for the so-called leading and the lagging strands. DNA synthesis proceeds from the 5' to the 3' DNA ends, but native (double-stranded) DNA is a polar molecule; that is, the leading strand has a 5'-3' orienta tion, whereas the lagging strand has a 3'-5' orientation. Therefore, although in the leading strand the synthesis of new DNA is straightforward, the process becomes more complicated in the lagging strand. Semiconservative DNA replication requires a labile short RNA primer to begin DNA polymerization in the 5'-to-3' direction, in the lagging strand. After DNA polymerization, the RNA primers are degraded and replaced by DNA synthesized from an upstream primer. Because there is no DNA beyond the end of the chromosome to serve as a template for an RNA priming event, the gap between the final lagging strand segment (Okazaki fragment) and the end of the chromosome cannot be filled in (the "end replication problem"). Thus the 5' end of the lagging strand will lose some nucleotides each time a cell replicates its DNA (Figure 2.2). Thus, the extreme end of a chromosome is not replicated and progressively shortens. This end, called the telomere (telos = end, meros = part), is made of repeats of 6 base pairs: (TTAGGG)n on one strand and (AATCCC)n on the complementary DNA strand. Human telomeres vary in length with age and cell type, with a range of 6 to 12 kilobase pairs (kbp: 6000-12,000 bp) in somatic cells. With the mechanism of Okazaki fragment replication, 50 to 100 bp are usually lost with each cell cycle. More important, loss of telomeric DNA continues with successive cell divisions until the telomeres reach such a critically short length that replication is halted. This happens, on average, after 60 to 70 divisions in human cells, and at this point the cell stops growing and enters senescence.
^ DNA replication
RNA primer i
Okazaki fragment (OF)
RNA primer I Removal + ^ OF ligation
Shortening of chromosome ends
FIGURE 2.2. Mechanism of telomere shortening with advancing replicative age of the cell (the "end replication problem").
The fundamental issue concerning telomeres and their relationship with aging is the idea that progressive telomere shortening represents a biologic or mitotic clock of the cell keeping track of the number of replications a cell has used and indicating the time for permanent growth arrest when telomeres are sufficiently short. Telomere function is strictly associated with the function of the related enzyme, telomerase. Telomerase is a reverse transcriptase (i.e., an enzyme capable of synthesizing DNA starting from a template made of RNA) that can add TTAGGG examers to chromosome ends, thus extending and maintaining the length of telomeres and, as a consequence, the number of divisions a cell may undergo.
The most outstanding discovery concerning the telomere-telomerase system is that nearly the complete spectrum of human tumors has been shown to be telomerase positive, thus implying that tumor cells use telomerase to gain the capacity for unlimited proliferation and thus immortality. An exhaustive list of telomerase-positive human cancers has been reported by Granger et al.27 The discovery of the appearance of telomerase activity as a distinctive feature of cancer in comparison to normally growing cells has opened new horizons in both diagnosis and treatment of cancer, since cancer cells can be identified for their distinctive expression of the enzyme telomerase, which in not expressed by normal cells and can be treated with telomerase inhibitors to "induce" cell senescence. This model assumes that because many divisions are needed to accumulate all the changes needed to transform a normal cell into a cancerous one,28,29 cell senescence acts as an initial "cancer brake."
At this point it must be emphasized that telomer-ase is not the only tool a cell can use to lengthen its proliferative capacity; other mechanisms, which effect alternative lengthening of telomeres (ALT), have been identified.30 Increasing the proliferative potential by either telomerase or ALT pathway is only one aspect of the process of malignant transformation.31 As reported by Granger et al.,27 there are at least six essential alterations necessary for malignancy shared by virtually all types of cancer. These are the generation of self-stimulatory growth signals, insensitivity to inhibitory growth signals, resistance to apoptosis, unlimited potential for proliferation (telomere lengthening), capacity for angiogenesis, and tissue invasion and metastasis. Whatever the implications of these arguments, the role of telomere shortening in proliferative aging remains unquestionable, as does the role of telo-mere lengthening in increasing the proliferative potential of the cell.
The final picture that can be inferred from major investigations concerning telomere physiology and pathology sounds rather paradoxical with respect to the introductory statement of this section. As a matter of fact, it is assumed from these investigations that the progressive shortening of telomeres is indicative of progressive cell senescence, and cell senescence, in turn, acts as a "cancer brake," theoretically allocating cancer and aging at the two opposite ends of the same spectrum. This seems to imply that, at the cellular level, the notion that advancing age is the most potent of all carcinogens is absolute nonsense.
Once again, the research on the role of chromosomal ploidy and genome stability in cancer and speci-ation gives us insight into a possible unifying theory to solve the apparent paradox concerning the role of aging in cancer in the light of telomere dynamics. In summary, it has been found that telomere shortening (and thus cell aging), plays an important role in genetic instability, including chromosomal loss, reciprocal translocations, and cancer development.32 These observations have led authors to propose that the following sequence of events in cancer transformation is related to telomere dynamics. In ordinary somatic cells, certain chromosomes may lose or have reduced amounts of telomeric DNA (aging) and, therefore, may undergo translocations or other structural alterations. Because of this DNA rearrangement, cells get arrested in the G2/M phase of their life cycle. Their chromosomes replicate, but the cytoplasm does not, thus resulting in tetraploidy (four copies of the normal eu-ploid number of chromosomes) and, if this continues in the absence of telomerase, the cell undergoes apop-tosis. On the other hand, it may happen that telomeres are stabilized because of activation or upregulation of telomerase or other pathways (ALT), in which case the cell will survive and push to undergo mitosis. The high number of chromosomes within this cell, and the presence of only two centrosomes will trigger the amplification of other centrosomes to allow the cell to divide. (Centrosomes are the structures joining the two chromosomes of a couple within the cell. Their function is to help organize the mitotic spindle, which is the collection of microtubules that pull the duplicated chromosomes apart during cell division, ensuring that each of the two daughter cells has received the same number of chromosomes.) At this point, the cell will show a number of structural anomalies, including telomere erosion, double chromosome number, and amplification of centrosomes. This will give rise to multipolar mitosis, aneuploidy, and subsequent cancer formation.33 In light of this view, telomere erosion due to cell senescence is the key factor in inducing the genome instability that represents the hallmark of malignant transformation, and the telo-merase- or ALT-dependent lengthening of telomeres intervenes in a second phase of malignant transformation to confer on the cell the capacity to overcome the apoptotic pathway and push toward mitosis and consequent expansion of the structural abnormalities to future generations. This view seems to perfectly reconcile telomere dynamics with both aging and can cer and to validate the assumption that aging is the most potent of all carcinogens.
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