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Cancer and Ageing: Rival Demons?

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Cancer and Ageing: Rival Demons? REVIEWS CANCER AND AGEING: RIVAL DEMONS? Judith Campisi Organisms with renewable tissues use a network of genetic pathways and cellular responses to prevent cancer. The main mammalian tumour-suppressor pathways evolved from ancient mechanisms that, in simple post-mitotic organisms, act predominantly to regulate embryogenesis or to protect the germline. The shift from developmental and/or germline maintenance in simple organisms to somatic maintenance in complex organisms might have evolved at a cost. Recent evidence indicates that some mammalian tumour-suppressor mechanisms contribute to ageing. How might this have happened, and what are its implications for our ability to control cancer and ageing? COMPLEX ORGANISMS Cancer afflicts COMPLEX ORGANISMS, such as mice and have been studied extensively, primarily in mice and Multicellular organisms that are humans, almost inevitably as they approach middle and humans. It is clear that at least two main strategies composed of both post-mitotic old age1–3 (FIG. 1; BOX 1). This is not the case for all organ- evolved to suppress cancer4. One mechanism uses and renewable (mitotic) somatic isms, however; the SIMPLE model invertebrate organisms CARETAKER proteins to protect the genome from acquiring tissues. Caenorhabditis elegans and Drosophila melanogaster,for potentially oncogenic mutations. The other uses SIMPLE ORGANISMS example, do not develop cancer. So, how prevalent is can- GATEKEEPER proteins to eliminate or prevent the growth of Multicellular organisms that are cer among animals, and what distinguishes organisms potential cancer cells (FIG. 2). Both mechanisms evolved composed entirely or largely of that develop cancer from those that do not? from ancestral genetic pathways, elements of which were, post-mitotic somatic cells. and still are, present in simple organisms that do not CARETAKERS Tumour-suppressor mechanisms develop cancer. Tumour-suppressor genes or Whether multicellular organisms are subject to cancer An important distinction between caretaker and proteins that act to protect the depends to some extent on whether they are simple or gatekeeper tumour suppressors is that caretakers gen- genome from damage or complex. An important distinction between simple and erally operate within the context of the cell, whereas mutations. Many caretaker genes encode proteins that recognize complex organisms is that complex organisms have gatekeepers operate within the context of the tissue or repair DNA damage. renewable tissues that are essential for viability, and this or organism. That is, caretakers act to preserve cellu- might explain their susceptibility to cancer. Renewable lar integrity and survival, whereas gatekeepers cause tissues allow adult organisms to replace cells that are lost cell death or loss of cell-division potential for the through stochastic, pathological or catastrophic dam- good of the organism. Consistent with this general age, or through differentiation. However, the cell prolif- distinction, the origin of many (but certainly not all) Lawrence Berkeley National eration that occurs in renewing tissues puts the genome caretakers can be traced back to genes that are present Laboratory, Life Sciences at great risk for acquiring and propagating mutations in simple single-celled organisms. So, many caretaker Division, 1 Cyclotron Road, Berkeley, California that can confer malignant characteristics on cells (BOX 1). genes encode proteins that participate in evolutionar- 94720, USA; and So, it seems that, as complex organisms with renewable ily conserved, genomic maintenance functions, such Buck Institute for Age tissues evolved, so did the risk of cancer. as DNA-repair pathways. These include RECQ-like Research, 8001 Redwood Complex organisms evolved strategies — tumour- helicases, components of the NUCLEOTIDE EXCISION REPAIR Boulevard, Novato, California 94945, USA. suppressor mechanisms — to suppress the development pathway and TELOMERE maintenance proteins. By e-mail: [email protected] of cancer, at least through the period of sexual maturity contrast, many gatekeeper tumour-suppressor genes doi:10.1038/nrc1073 and reproduction (young adulthood). These mechanisms do not exist in single-celled organisms, but appear NATURE REVIEWS | CANCER VOLUME 3 | MAY 2003 | 339 © 2003 Nature Publishing Group REVIEWS Summary Tumour suppression and longevity Tumour-suppressor genes prevent premature death • Cancer is a problem that affects organisms with renewable tissues; these have from cancer, so it stands to reason that they should also evolved tumour-suppressor mechanisms to suppress the development of cancer. be classified as LONGEVITY-assurance genes — genes that • Tumour-suppressor genes act to prevent or repair genomic damage (caretakers), slow the AGEING process and promote the health and sur- or inhibit the propagation of potential cancer cells (gatekeepers) by permanently vival of adult organisms5. Indeed, this is probably the arresting their growth (cellular senescence) or inducing cell death (apoptosis). case for caretaker tumour suppressors, but recent find- • Some caretaker tumour suppressors seem to postpone the development of ings raise the possibility that some gatekeeper tumour ageing phenotypes, and so are also longevity-assurance genes. suppressors can actually contribute to the development • The gatekeeper tumour-suppressor mechanisms (apoptosis and cellular of AGEING PHENOTYPES in complex organisms. What are the senescence), by contrast, might promote certain ageing phenotypes. relationships between tumour-suppressor and • Apoptosis and cellular senescence are controlled by the p53 and RB tumour- longevity-assurance genes, and how might tumour sup- suppressor pathways, components of which are evolutionarily conserved among pressors have both beneficial (preventing cancer) and multicellular organisms. detrimental (promoting ageing) effects? Regardless of whether tumour suppressors are care- • The evolutionary hypothesis of antagonistic pleiotropy predicts that some takers or gatekeepers, inactivating mutations increase processes that benefit young organisms (by suppressing cancer, for example) can have detrimental effects later in life and would therefore contribute to ageing. the risk for developing cancer. Therefore, all tumour suppressors should directly promote the longevity of • Both apoptosis and cellular senescence might be antagonistically pleiotropic, complex muticellular organisms by curtailing the devel- promoting ageing by exhausting progenitor or stem cells.Additionally, opment of malignant tumours, and loss of tumour-sup- senescent cells secrete factors that can disrupt tissue integrity and function, and pressor function should shorten the average lifespan by even promote the progression of late-life cancers. increasing the incidence of cancer. • Recent studies on p53 provide a molecular basis for how tumour suppression Numerous lines of evidence, particularly from and ageing might be intertwined. mouse models and human genetics, support this obvi- ous and direct relationship between tumour-suppressor mechanisms and longevity6–16. However, recent findings with the evolution of muticellular organisms. indicate that a more complex relationship exists — GATEKEEPERS Examples include the genes that encode the p53 and tumour-suppressor mechanisms can influence ageing, Tumour-suppressor genes or RB proteins, which control the cellular responses of which ultimately limits longevity. The links between proteins that regulate cellular APOPTOSIS and CELLULAR SENESCENCE. tumour suppression and ageing are twofold. responses that prevent the First, some tumour-suppressor mechanisms not survival or proliferation of only curtail cancer, but also seem to retard the appear- potential cancer cells. These responses are known as ance of specific ageing phenotypes. Recent findings Mice Humans apoptosis and cellular 0 100 show that defects in certain DNA-repair pathways senescence, respectively. increase both the incidence of cancer and the rate at which specific ageing phenotypes develop17. These NUCLEOTIDE EXCISION REPAIR A DNA-repair pathway that findings support the idea that DNA damage and loss removes and replaces damaged of genomic integrity in somatic cells can contribute to nucleotides, particularly those ageing phenotypes other than cancer18. So, some care- that distort the DNA helix. Survival (%) taker tumour suppressors might act as longevity- assurance genes, independently of their role in TELOMERES Cancer incidence (%) The DNA–protein structure that tumour suppression. stabilizes the ends of linear 100 0 Conversely, recent evidence indicates that other chromosomes and protects them 1.5 3 60 120 tumour-suppressor mechanisms, particularly the from degradation or fusion. In Age (years) gatekeeper mechanisms of apoptosis and cellular vertebrates, telomeres are Cancer incidence senescence, dually suppress the development of cancer composed of several-kilobase Survival pairs of the sequence TTTAGGG and promote the development of specific ageing phe- and several associated proteins. Figure 1 | Cancer increases with ageing. Cancer incidence notypes. These findings raise the possibility that some (although not necessarily death from cancer) rises exponentially tumour-suppressor genes show ANTAGONISTIC APOPTOSIS with age, beginning at about the mid-point of the maximum PLEIOTROPY19,20, and therefore contribute to ageing. Ordered, genetically 1–3 lifespan of the species . So, mice, which have a maximum Moreover, when caretaker mechanisms fail, the ageing
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